Guide : Dr.K. Vijayalakshmi
Co-Guide : Dr. T.N. Sathyaprabha
|Neurophysiology @ NIMHANS||
Rashmi savant presented her PhD work progress. The title of the PhD thesis was 'A study on the mechanisms of action of Chitotriosidase-1 - relevance to pathophysiology of sporadic ALS'.
Guide : Dr.K. Vijayalakshmi
Co-Guide : Dr. T.N. Sathyaprabha
JC - LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease
Aditi opened the Journal Club presentations for the new academic year. The paper was from PNAS journal.
Exploring dysfunctional cellular mechanisms in neuro-degenerative diseases provides insight to mechanism of the disorder. The paper demonstrated a novel interatcion between LRRK2 and auxilin genes and how they bring about dopamine mediated toxicity in PD.
Synaptic vesicle pools are recovered at the axon terminal through clathrin mediated endocytosis. This entire process is tightly controlled by phosphoregulated proteins. After pinching off, auxilin binds to a new clathrin coated vesicle and recruits hsc70 to remove the clathrin clutch. This results in producing a synaptic vesicle that can be packaged with neurotransmitters.
Defective synaptic vesicle endocytosis in substantia nigra pars compacta dopaminergic neurons couldead to increased levels of cytosolic dopamine. These excess dopamine get oxidised and trigger a cascade of toxic effects. The study demonstrated that LRRK2 mediated phosphorylation of auxin at Ser627 location in a clathrin coated vesicle disrupts endocytosis process. This will result in lot many uncoated vesicles in pre-synaptic terminal and reduced functional synaptic vesicle density.
1. The mutant LRRK2 gene which sits in 12th chromosome in humans is a concern for google CEO, Sergey Brin.
2. When a resupply mission lifts off in August bound for the International Space Station, it will be carrying an important cargo for researchers studying Parkinson’s disease: A protein considered to be a key to potential future therapies
Raghava kick started 2018's seminar series with the topic "Dynamics of Synaptic Transmission".
The talk started with basics of synaptic transmission covering pre and post synaptic dynamics. LTP was taken as an example to explain the dynamics.
Salient discussions of the talk:
In her seminar, Rukmani MR discussed the challenges surrounding Multiple System Atrophy (MSA). This is a relatively rare disorder (1.9 to 4.9 per 100,000), has an adult onset. NIMHANS gets a few cases every month.
Diagnosis is difficult and typically done by ruling out Parkinsons Disease (PD) or Spinocerebellar ataxia (SCA). Symptoms include autonomic dysfunctions (supine hypertension and orthostatic hypotension, urinary incontinence). The disease leads to selective neuronal loss, myelin pallor, possible microglial activation and usually involves caudate, putamen, substantia nigra and cerebellum. Neuroimaging does show marked features in the putamen and 'hot cross bun' sign in the pons but these are not specific only to MSA. There are two broad groups MSA-P with more PD like features of bradykinesia and resting tremor and MSA-C with more limb/gait ataxia features. Treatment is symptomatic and definitive diagnosis is possible only post mortem (seen by high density oligodendroglial cytoplasmic inclusions).
Vidyadhara DJ presented the work done so far on the MPTP mouse model of Parkinson's Disease.
Rashmi Savant (Ph.D Scholar) conducted a journal club discussion on the paper titled Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis by Song, Miranda, Braun et al published in Nature Medicine Volume 22 - Number 4 - April 2016.
Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.
Anshu Jha (Ph.D Scholar) presented the paper Graded Neuronal Modulations Related to Visual Spatial
Attention by J. Patrick Mayo & John H. R. Maunsell published in the Journal of Neuroscience, May 11, 2016 36(19):5353–5361.
Studies of visual attention in monkeys typically measure neuronal activity when the stimulus event to be detected occurs at a cued location versus when it occurs at an uncued location. But this approach does not address how neuronal activity changes relative to conditions where attention is unconstrained by cueing. Human psychophysical studies have used neutral cueing conditions and found that neutrally cued behavioral performance is generally intermediate to that of cued and uncued conditions (Posner et al., 1978; Mangun and Hillyard, 1990; Montagna et al., 2009). To determine whether the neuronal correlates of visual attention during neutral cueing are similarly intermediate, we trained macaque monkeys to detect changes in stimulus orientation that were more likely to occur at one location (cued) than another (uncued), or were equally likely to occur at either stimulus location (neutral). Consistent with human studies, performance was best when the location was cued, intermediate when both locations were neutrally cued, and worst when the location was uncued. Neuronal modulations in visual area V4 were also graded as a function of cue validity and behavioral performance. By recording from both hemispheres simultaneously, we investigated the possibility of switching attention between stimulus locations during neutral cueing. The results failed to support a unitary “spotlight” of attention. Overall, our findings indicate that attention-related changes in V4 are graded to accommodate task demands.
Dr. Pranay S. Yadav (M.Phil. Scholar) presented a seminar on Regulation of Respiration with special reference to pacemaker cells of the pre-Bötzinger Complex.
Taking a reductionist approach, discussion proceeded from the most directly observable behaviour - breathing, to the microcircuit-level mechanistic models that explain rhythmogenesis. Key areas of discussion gravitated towards the following:
~ Rhythmogenicity - Pacemaker Hypothesis vs Group Pacemaker Hypothesis
~ Oscillatory Bursting Mechanisms:
- Persistent Sodium Current-dependent [INaP] burst generation
- Calcium-activated non-selective Cationic Current-dependent [ICaN] burst generation
Dr. Siju Vikhnan (M.Phil. Scholar) presented a seminar on Neurotransmitter Release.
Discussion progressed from a gross overview of neurotransmitters, to the mechanistic processes involved in neurotransmission, focusing on topics like:
Orthostatic Hypertension & Cardiac Sympathetic Denervation in Parkinson's Disease with REM Sleep Behavioral Disorder - Journal Club
Dr. Rukmani M. R. (Ph.D Scholar) presented the paper Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder by Kim J, Park H, Oh Y, Lee S, Park J, Son B, Lee K. published in the Journal of the Neurological Sciences. 362 (2016). 59-63.
Background: Rapid eye movement (REM) sleep behavioral disorder (RBD), orthostatic hypotension (OH), and cardiac sympathetic denervation were commonly observed in PD and are related in both the premotor and motor periods. This study is intended to evaluate if the OH and cardiac sympathetic denervation found in PD are associated with RBD.
Methods: Among 94 non-medicated and mild PD patients, 53 had RBD. Orthostatic vital signs and ambulatory 24-hour blood pressure values were recorded. 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy as obtained in all patients. The association between orthostatic hypotension, supine hypertension, nocturnal hypertension, non-dipping, myocardial MIBG uptake, and RBD was analyzed.
Results: RBD was associated with orthostatic hypotension. Patients with RBD had higher systolic blood pressure changes during orthostasis and lower myocardial MIBG uptake than patients without RBD and controls. Patients with OH also had lower mean H/M ratios those in the non-OH group.
Conclusion: This study showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. This association may be closely correlated with Braak alpha-synuclein patho-
genetic sequences, which would account for the clinical spectrum of PD.