Biomedical subjects
M J Todd
Publications and source records attributed to M J Todd.
Chaperonin-facilitated protein folding: optimization of rate and yield by an iterative annealing mechanism.
We develop a heuristic model for chaperonin-facilitated protein folding, the iterative annealing mechanism, based on theoretical descriptions of "rugged" conformational free energy landscapes for protein folding, and on experimental evidence that (i) folding proceeds by a nucleation mechanism whereby correct and incorrect nucleation lead to fast and slow folding kinetics, respectively, and (ii) chaperonins optimize the rate and yield of protein folding by an active ATP-dependent process. The chaperonins GroEL and GroES catalyze the folding of ribulose bisphosphate carboxylase at a rate proportional to the GroEL concentration. Kinetically trapped folding-incompetent conformers of ribulose bisphosphate carboxylase are converted to the native state in a reaction involving multiple rounds of quantized ATP hydrolysis by GroEL. We propose that chaperonins optimize protein folding by an iterative annealing mechanism; they repeatedly bind kinetically trapped conformers, randomly disrupt their structure, and release them in less folded states, allowing substrate proteins multiple opportunities to find pathways leading to the most thermodynamically stable state. By this mechanism, chaperonins greatly expand the range of environmental conditions in which folding to the native state is possible. We suggest that the development of this device for optimizing protein folding was an early and significant evolutionary event.
Glutamate receptor agonist injections into the dorsal striatum cause contralateral turning in the rat: involvement of kainate and AMPA receptors.
Unilateral stimulation of glutamate receptors in the dorsal striatum of intact rats resulted in contralateral turning. Turning behavior was recorded for 20 min following unilateral intrastriatal injections (0.5 microliter) in chronically cannulated rats. Kainate injections caused a dose-dependent increase in contralateral rotation that was blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), the action potential blocker tetrodotoxin, and by increasing doses of the dopamine receptor antagonist cis-flupenthixol. Injections of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) also caused rotation that was blocked with co-injections of CNQX, tetrodotoxin or cis-flupenthixol. Neither CNQX nor tetrodotoxin injected alone caused turning. This effect is dopamine-dependent, and may result from a kainate or AMPA-induced increase in dopamine release. Glutamate receptor agonist injections into the striatum may cause contralateral turning by degrading information in ascending cortical projections and may further influence locomotion via basal ganglia output nuclei projections to the brainstem.
GroE structures galore.
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Three-dimensional vector analysis of the human vestibuloocular reflex in response to high-acceleration head rotations. I. Responses in normal subjects.
1. The kinematics of the human angular vestibuloocular reflex (VOR) in three dimensions was investigated in 12 normal subjects during high-acceleration head rotations (head "impulses"). A head impulse is a passive, unpredictable, high-acceleration (3,000-4,000 degrees/s2) head rotation of approximately 10-20 degrees in roll, pitch, or yaw, delivered with the subject in the upright position and focusing on a fixation target. Head and eye rotations were measured with dual search coils and expressed as rotation vectors. The first of these two papers describes a vector analysis of the three-dimensional input-output kinematics of the VOR as two indexes in the time domain: magnitude and direction. 2. Magnitude is expressed as speed gain (G) and direction as misalignment angle (delta). G is defined as the ratio of eye velocity magnitude (eye speed) to head velocity magnitude (head speed). delta is defined as the instantaneous angle by which the eye rotation axis deviates from perfect alignment with the head rotation axis in three dimensions. When the eye rotation axis aligns perfectly with the head rotation axis and when eye velocity is in a direction opposite to head velocity, delta = 0. The orientation of misalignment between the head and the eye rotation axes is characterized by two spatial misalignment angles, which are the projections of delta onto two orthogonal coordinate planes that intersect at the head rotation axis. 3. Time series of G were calculated for head impulses in roll, pitch, and yaw. At 80 ms after the onset of an impulse (i.e., near peak head velocity), values of G were 0.72 +/- 0.07 (counterclockwise) and 0.75 +/- 0.07 (clockwise) for roll impulses, 0.97 +/- 0.05 (up) and 1.10 +/- 0.09 (down) for pitch impulses, and 0.95 +/- 0.06 (right) and 1.01 +/- 0.07 (left) for yaw impulses (mean +/- 95% confidence intervals). 4. The eye rotation axis was well aligned with head rotation axis during roll, pitch, and yaw impulses: delta remained almost constant at approximately 5-10 degrees, so that the spatial misalignment angles were < or = 5 degrees. delta was 9.6 +/- 3.1 (counterclockwise) and 9.0 +/- 2.6 (clockwise) for roll impulses, 5.7 +/- 1.6 (up) and 6.1 +/- 1.9 (down) for pitch impulses, and 6.2 +/- 2.2 (right) and 7.9 +/- 1.5 (left) for yaw impulses (mean +/- 95% confidence intervals). 5. VOR gain (gamma) is the product of G and cos(delta). Because delta is small in normal subjects, gamma is not significantly different from G. At 80 ms after the onset of an impulse, gamma was 0.70 +/- 0.08 (counterclockwise) and 0.74 +/- 0.07 (clockwise) for roll impulses, 0.97 +/- 0.05 (up) and 1.09 +/- 0.09 (down) for pitch impulses, and 0.94 +/- 0.06 (right) and 1.00 +/- 0.07 (left) for yaw impulses (mean +/- 95% confidence intervals). 6. VOR latencies, estimated with a latency shift method, were 10.3 +/- 1.9 (SD) ms for roll impulses, 7.6 +/- 2.8 (SD) ms for pitch impulses, and 7.5 +/- 2.9 (SD) ms for yaw impulses. 7. We conclude that the normal VOR produces eye rotations that are almost perfectly compensatory in direction as well as in speed, but only during yaw and pitch impulses. During roll impulses, eye rotations are well aligned in direction, but are approximately 30% slower in speed.
Three-dimensional vector analysis of the human vestibuloocular reflex in response to high-acceleration head rotations. II. responses in subjects with unilateral vestibular loss and selective semicircular canal occlusion.
1. We studied the three-dimensional input-output human vestibuloocular reflex (VOR) kinematics after selective loss of semicircular canal (SCC) function either through total unilateral vestibular deafferentation (uVD) or through single posterior SCC occlusion (uPCO), and showed large deficits in magnitude and direction in response to high-acceleration head rotations (head "impulses"). 2. A head impulse is a passive, unpredictable, high-acceleration (3,000-4,000 degrees/s2) head rotation through an amplitude of 10-20 degrees in roll, pitch, or yaw. The subjects were tested while seated in the upright position and focusing on a fixation target. Head and eye rotations were measured with the use of dual search coils, and were expressed as rotation vectors. A three-dimensional vector analysis was performed on the input-output VOR kinematics after uVD, to produce two indexes in the time domain: magnitude and direction. Magnitude is expressed as speed gain (G) and direction as misalignment angle (delta). 3. G. after uVD, was significantly lower than normal in both directions of head rotation during roll, pitch, and yaw impulses, and were much lower during ipsilesional than during contralesional roll and yaw impulses. At 80 ms from the onset of an impulse (i.e., near peak head velocity), G was 0.23 +/- 0.08 (SE) (ipsilesional) and 0.56 +/- 0.08 (contralesional) for roll impulses, 0.61 +/- 0.09 (up) and 0.72 +/- 0.10 (down) for pitch impulses, and 0.36 +/- 0.06 (ipsilesional) and 0.76 +/- 0.09 (contralesional) for yaw impulses (mean +/- 95% confidence intervals). 4. delta, after uVD, was significantly different from normal during ipsilesional roll and yaw impulses and during pitch-up and pitch-down impulses. delta was normal during contralesional roll and yaw impulses. At 80 ms from the onset of the impulse, delta was 30.6 +/- 4.5 (ipsilesional) and 13.4 +/- 5.0 (contralesional) for roll impulses, 23.7 +/- 3.7 (up) and 31.6 +/- 4.4 (down) for pitch impulses, and 68.7 +/- 13.2 (ipsilesional) and 11.0 +/- 3.3 (contralesional) for yaw impulses (mean +/- 95% confidence intervals). 5. VOR gain (gamma), after uVD, were significantly lower than normal for both directions of roll, pitch, and yaw impulses and much lower during ipsilesional than during contralesional roll and yaw impulses. At 80 ms from the onset of the head impulse, the gamma was 0.22 +/- 0.08 (ipsilesional) and 0.54 +/- 0.09 (contralesional) for roll impulses, 0.55 +/- 0.09 (up) and 0.61 +/- 0.09 (down) for pitch impulses, and 0.14 +/- 0.10 (ipsilesional) and 0.74 +/- 0.06 (contralesional) for yaw impulses (mean +/- 95% confidence intervals). Because gamma is equal to [G*cos (delta)], it is significantly different from its corresponding G during ipsilesional roll and yaw, and during all pitch impulses, but not during contralesional roll and yaw impulses. 6. After uPCO, pitch-vertical gamma during pitch-up impulses was reduced to the same extent as after uVD; roll-torsional gamma during ipsilesional roll impulses was significantly lower than normal but significantly higher than after uVD. At 80 ms from the onset of the head impulse, gamma was 0.32 +/- 0.13 (ipsilesional) and 0.55 +/- 0.16 (contralesional) for roll impulses, 0.51 +/- 0.12 (up) and 0.91 +/- 0.14 (down) for pitch impulses, and 0.76 +/- 0.06 (ipsilesional) and 0.73 +/- 0.09 (contralesional) for yaw impulses (mean +/- 95% confidence intervals). 7. The eye rotation axis, after uVD, deviates in the yaw plane, away from the normal interaural axis, toward the nasooccipital axis, during all pitch impulses. After uPCO, the eye rotation axis deviates in same direction as after uVD during pitch-up impulses, but is well aligned with the head rotation axis during pitch-down impulses.
The single-ring Thermoanaerobacter brockii chaperonin 60 (Tbr-EL7) dimerizes to Tbr-EL14.Tbr-ES7 under protein folding conditions.
Chaperone proteins assist in the folding of some newly synthesized proteins and inhibit protein aggregation. The Thermoanaerobacter brockii chaperonin proteins (Tbr-EL and Tbr-ES) have recently been purified and characterized [Truscott, W.N., Høj, P. B., & Scopes, R. K. (1994) Eur. J. Biochem. 222, 277-284]; Tbr-EL was a single seven-membered toroid, unlike most GroELs which exist as double toroids. Using high-resolution gel filtration chromatography, we have resolved the purified Tbr-EL into single ringed (Tbr-EL7) and double ringed (Tbr-EL14) species. The latter contained tightly bound Tbr-ES co-chaperonin (Tbr-EL14.Tbr-ES7). In the presence of Mg.ATP and either Escherichia coli GroES (Eco-ES) or Tbr-ES (i.e., under protein folding conditions), the isolated Tbr-EL7 rapidly dimerized to the Tbr-EL14.Eco-ES7 or Tbr-EL14.Tbr-ES7 complexes. The doubly toroidal species thus formed contained > or = 6 molecules tightly bound ADP and one GroES7 and are similar to the asymmetric chaperonin complex isolated from Thermus thermophilus [Taguch, H., Konishi, J., Ishii, N., & Yoshida, M. (1991) J. Biol. Chem. 266, 22411-22418]. The isolated Tbr-EL7 and Tbr-EL14.Tbr-ES7 hydrolyzed ATP at approximate to 2 and 1 min-1, respectively. Addition of a molar excess of Eco-ES7 to the isolated Tbr-EL7 reduced the ATPase activity to 1 min-1, consistent with the formation of Tbr-EL14.Eco-ES7. Eco-ES7 failed to inhibit the Tbr-El14.Tbr-ES7 complex. The isolated Tbr-EL14.Tbr-ES7 complex did not support the folding of Rubisco under nonpermissive conditions. Only when the complex was supplemental with additional GroES was folding of Rubisco observed; i.e., one molar equivalent of GroES was not sufficient for folding. Both Tbr-EL7 and Tbr-EL14.Tbr-ES7 bound on unfolded [35S] Rhodospirillum rubrum Rubisco per mole particle. In contrast, Eco-EL14 bound 2 mol of protein per mole particle, consistent with each toroid having a peptide binding site. Eco-EL14.Eco-ES7 complex only bound one unfolded protein, thus GroES binding blocks one GroEL peptide binding site. Addition of Eco-ES7 to a Eco-EL14.Rubisco2 complex did not result in the displacement of one molecule of Rubisco but in the formation of a ternary Eco-EL14.Rubisco2.Eco-ES7 complex.
On the distribution of ligands within the asymmetric chaperonin complex, GroEL14.ADP7.GroES7.
In the presence of MgATP or MgADP the E. coli chaperonin proteins, GroEL and GroES, form a stable asymmetric complex with a stoichiometry of two GroEL7:one GroES7: seven MgADP. The distribution of the ligands between the two heptameric GroEL rings is crucial to our understanding of the mechanism of chaperonin-assisted folding, being either cis (i.e. [GroEL7.MgADP7.GroES7]-[GroEL7]) or trans (i.e. [GroEL7.MgADP7]-[GroEL7.GroES7]. On the basis of cross-linking experiments with 8-azido-ATP and the heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), it was suggested that GroES and MgADP are bound to the same GroEL ring which resists proteinase K digestion [Nature 366 (1993) 228-233]. However, we find that the SPDP-promoted cross linking of GroES and GroEL occurs in the absence of Mg2+, ADP or ATP, which are required for the formation of the asymmetric complex. Cross-linking is shown to occur only when the SPDP-modified GroES is co-precipitated with GroEL by trichloracetic acid. Furthermore, there are structural grounds for questioning whether SPDP can crosslink, in a physiologically relevant manner, an amino group of GroES with any of the cysteinyl groups of GroEL.
Stability of the asymmetric Escherichia coli chaperonin complex. Guanidine chloride causes rapid dissociation.
The chaperonin proteins, GroEL14 and GroES7, inhibit protein aggregation and assist in protein folding in a potassium/ATP-dependent manner. In vitro, assays for chaperonin activity typically involve adding a denatured substrate protein to the chaperonins and measuring the appearance of correctly folded substrate protein. The influence of denaturant is generally ignored. Low concentrations of guanidinium chloride (< 100 mM) had a profound effect on the activity/structure of the chaperonins. Guanidinium decreased the ATPase activity of GroEL and attenuated the inhibition of GroEL ATP hydrolysis by GroES. The stable, asymmetric chaperonin complex which forms in the presence of GroES and ADP (GroES7.ADP7.GroEL7-GroEL7) rapidly dissociated upon addition of 80 mM guandinium chloride. Dissociation was enhanced at high ionic strength, but rapid dissociation was guanidinium-specific. Accelerated release of the GroES from the complex was also demonstrated. Unfolded proteins alone had no effect on complex stability. Residual guanidinium depressed the rate of Rhodospirillum rubrum ribulose-1,5-bisphosphate carboxylase (Rubisco) folding; an increased aggregation rate also decreased the yield of folded Rubisco. Chaperonin-assisted folding is therefore best studied using proteins denatured by means other than guanidinium chloride.
GroES and the chaperonin-assisted protein folding cycle: GroES has no affinity for nucleotides.
The E. coli chaperonin proteins, GroEL and GroES, assist in folding newly synthesized proteins. GroES is necessary for GroEL-assisted folding under conditions where the substrate protein cannot spontaneously fold. On the basis of photolabelling of GroES with 8-azido-ATP, a role for nucleotide binding to GroES in chaperonin function was suggested [Martin, et al., Nature, 366 (1993) 279-282]. We confirm the photolabeling of GroES with 8-azido-ATP. However, other proteins not known to contain nucleotide binding sites also became photolabeled suggesting that labeling is non-specific. Using rigorous physical methods, isothermal calorimetry and equilibrium binding, no interaction between GroES and nucleotides could be detected. We conclude that GroES has no nucleotide binding site.
Compensation of the human vertical vestibulo-ocular reflex following occlusion of one vertical semicircular canal is incomplete.
The vestibulo-ocular reflex (VOR) was studied in nine human subjects 2-15 months after permanent surgical occlusion of one posterior semicircular canal. The stimuli used were rapid, passive, unpredictable, low-amplitude (10-20 degrees), high-acceleration (3000-4000 degrees/s2) head rotations in pitch and yaw planes. The responses measured were vertical and horizontal eye rotations, and the results were compared with those from 19 normal subjects. After unilateral occlusion of the posterior semicircular canal, the gain of the head-up pitch vertical VOR--the vertical VOR generated by excitation from only one and disfacilitation from two vertical semicircular canals--was reduced to 0.61 +/- 0.06 (normal 0.92 +/- 0.06) at a head velocity of 200 degrees/s. In contrast the gain of the head-down pitch vertical VOR--the VOR still generated by excitation from two, but disfacilitation from only one vertical semicircular canal--was within normal limits: 0.86 +/- 0.11 (normal 0.96 +/- 0.04). The gain of the horizontal VOR in response to yaw head rotations--ipsilesion 0.81 +/- 0.06 (normal 0.88 +/- 0.05) and contralesion 0.80 +/- 0.11 (normal 0.92 +/- 0.11)--was within normal limits in both directions (group means +/- two-tailed 95% confidence intervals given in each case). These results show that occlusion of just one vertical semicircular canal produces a permanent deficit of about 30% in the vertical VOR gain in response to rapid pitch head rotations in the excitatory direction of the occluded canal. This observation indicates that, in response to a stimulus in the higher dynamic range, compensation of the human VOR for the loss of excitatory input from even one vertical semicircular canal is incomplete.
Torsional eye velocity components during yaw angular acceleration identify the side of unilateral vestibular deafferentation.
Using dual torsion scleral search coils we have recorded 3-dimensional eye position during yaw angular accelerations of 20 degrees/s2 about an earth vertical axis in healthy subjects and in patients with unilateral vestibular deafferentation (UVD). These experiments produced two interesting results: i) even in healthy subjects, the axis of eye velocity did not coincide with the (earth vertical) stimulus axis during centred rotation; ii) Patients with UVD had torsional eye velocity components that were systematically different from those in normal subjects. While in normals the direction of the torsional component of the eye velocity depended on the direction of rotation and was on average approximately symmetric for CW and CCW yaw rotation, there was a clear asymmetry in patients, which was distinctly different for left and right UVD.
The effect of unilateral posterior semicircular canal inactivation on the human vestibulo-ocular reflex.
The responses to rapid, passive, unpredictable, low amplitude (10-20 degrees), high acceleration (3,000-4,000 degrees/s2) head rotations were used to study the human vestibulo-ocular reflex (VOR) in pitch and yaw plane after unilateral posterior semicircular canal occlusion (uPCO) in 10 subjects. The results from these 10 uPCO subjects were compared with those from 18 normal subjects. The VOR gains at a head velocity of 200 degrees/s in the uPCO subjects were: pitch upward = 0.62 +/- 0.06, pitch downward = 0.87 +/- 0.11, yew ipsilesion = 0.78 +/- 0.06, yaw contralesion = 0.79 +/- 0.10 and in normal subjects were: pitch upward = 0.92 +/- 0.06, pitch downward = 0.96 +/- 0.04, yaw right = 0.88 +/- 0.05, yaw left = 0.91 +/- 0.12 (group means +/- twotailed 95% confidence intervals). The results showed that the pitch-vVOR gain was significantly (p < 0.05) decreased in response to upward head impulses whereas in response to downward, ipsilesion and contralesion head impulses were not significantly different (p > 0.05) from the normals. This study shows that there is 30% permanent residual deficit of the upward pitch-vVOR with an up-down asymmetry in pitch-vVOR gain following inactivation of a single posterior semicircular canal and that compensation of pitch-vVOR function is incomplete.
The effect of roll-tilt on ocular skew deviation.
Static roll-tilt of normal healthy subjects causes the ocular tilt reaction (OTR) one component of which is disconjugate vertical eye position (skew deviation). In this study the magnitude of skew was measured subjectively by the use of a computerized Hess test at three static roll-tilt angles (head erect, left ear down and right ear down) and two viewing distances (20 cm and 60 cm). The results showed that during static roll-tilt there was a small skew deviation, the magnitude of which was increased at close viewing distances.
Dynamics of the chaperonin ATPase cycle: implications for facilitated protein folding.
The Escherichia coli chaperonins GroEL and GroES facilitate protein folding in an adenosine triphosphate (ATP)-dependent manner. After a single cycle of ATP hydrolysis by the adenosine triphosphatase (ATPase) activity of GroEL, the bi-toroidal GroEL formed a stable asymmetric ternary complex with GroES and nucleotide (bulletlike structures). With each subsequent turnover, ATP was hydrolyzed by one ring of GroEL in a quantized manner, completely releasing the adenosine diphosphate and GroES that were tightly bound to the other ring as a result of the previous turnover. The catalytic cycle involved formation of a symmetric complex (football-like structures) as an intermediate that accumulated before the rate-determining hydrolytic step. After one to two cycles, most of the substrate protein dissociated still in a nonnative state, which is consistent with intermolecular transfer of the substrate protein between toroids of high and low affinity. A unifying model for chaperonin-facilitated protein folding based on successive rounds of binding and release, and partitioning between committed and kinetically trapped intermediates, is proposed.
On the role of groES in the chaperonin-assisted folding reaction. Three case studies.
The mechanism by which correctly folded proteins are recovered from stable complexes with groEL is not well understood. Certain target proteins require ATP and groES, while others seemingly dispense with the cochaperonin. Here, we examine the chaperonin-assisted folding of ribulose-1,5-bisphosphate carboxylase, malate dehydrogenase, and citrate synthase, three proteins that are believed to require both chaperonin components for successful reactivation. Surprisingly, in all cases, the need for groES depended on the folding environment. Under "non-permissive" conditions, where unassisted spontaneous folding could not occur, reactivation to the native state required the complete chaperonin system (e.g. groEL, groES, and MgATP). However, under "permissive" conditions where spontaneous folding could occur groES was no longer mandatory. Instead, upon the addition of ATP alone, all three target proteins could be released from groEL, in a form that was capable of reaching the native state. In the permissive setting, groES merely accelerated the rate of the ATP-dependent release process. The results suggest that the incompletely folded protein species that are released from groEL, in the absence of groES, are not necessarily committed to the native state. Similar to the unassisted folding reaction, they still partition between productive and unproductive folding pathways in an environment-dependent manner. It follows that the mechanistic contribution of the co-chaperonin, groES, and its physiological significance in cellular protein folding, could be entirely missed in a permissive in vitro environment.
Unilateral vestibular deafferentation causes permanent impairment of the human vertical vestibulo-ocular reflex in the pitch plane.
Rapid, passive, unpredictable, low-amplitude (10-20 degrees), high-acceleration (3000-4000 degrees/s2) head rotations were used to study the vertical vestibulo-ocular reflex in the pitch plane (pitch-vVOR) after unilateral vestibular deafferentation. The results from 23 human subjects who had undergone therapeutic unilateral vestibular deafferentation were compared with those from 19 normals. All subjects were tested while seated in the upright position. Group means and two-tailed 95% confidence intervals are reported for the pitch-vVOR gains in normal and unilateral vestibular deafferented subjects. In normal subjects, at a head velocity of 125 degrees/s the pitch-vVOR gains were: upward 0.89 +/- 0.06, downward 0.91 +/- 0.04. At a head velocity of 200 degrees/s, the pitch-vVOR gains were: upward 0.92 +/- 0.06, downward 0.96 +/- 0.04. There was no significant up-down asymmetry. In the 15 unilateral vestibular deafferented subjects who were studied more than 1 year after unilateral vestibular deafferentation, the pitch-vVOR was significantly impaired. At a head velocity of 125 degrees/s, the pitch-vVOR gains were: upward 0.67 +/- 0.11, downward 0.63 +/- 0.07. At a head velocity of 200 degrees/s, the pitch-vVOR gains were: upward 0.67 +/- 0.07, downward 0.58 +/- 0.06. There was no significant up-down asymmetry. The pitch-vVOR gain in unilateral vestibular deafferented subjects was significantly lower (P < 0.05) than the pitch-vVOR gain in normal subjects at the same head velocities. These results show that total, permanent unilateral loss of vestibular function produces a permanent symmetrical 30% (approximately) decrease in pitch-vVOR gain. This pitch-vVOR deficit is still present more than 1 year after deafferentation despite retinal slip velocities greater than 30 degrees/s in response to head accelerations in the physiological range, indicating that compensation of pitch-vVOR function following unilateral vestibular deafferentation remains incomplete.
Jerk-waveform see-saw nystagmus due to unilateral meso-diencephalic lesion.
See-saw nystagmus is an uncommon but highly characteristic eye movement disorder comprising intorsion and elevation of one eye, with synchronous extorsion and depression of the other. It generally has a pendular waveform and is due to a midline, extrinsic, suprasellar mass lesion compressing or invading the brainstem bilaterally at the meso-diencephalic junction. This report deals with the clinical and MRI findings in three patients (and binocular three-dimensional quantitative oculographic findings in one patient) with a jerk waveform see-saw nystagmus due in each case to a unilateral meso-diencephalic lesion. In each patient the torsional component of the nystagmus fast phases rotated the upper poles of the eyes toward the side of the lesion. Jerk see-saw nystagmus can be clinically indistinguishable from pendular see-saw nystagmus and from the torsional-vertical nystagmus which occurs with medullary lesions. We propose that jerk see-saw nystagmus is due to unilateral inactivation of the torsional eye-velocity integrator, thought to be in the interstitial nucleus of Cajal, with sparing of the torsional fast-phase generator, thought to be in the adjacent rostral interstitial nucleus of the medial longitudinal fasciculus.