Vidyadhara DJ presented the work done so far on the MPTP mouse model of Parkinson's Disease.
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.
Yarreiphang (PhD Scholar) presented the progress of his ongoing PhD research in the areas of Parkinson's Disease using an MPTP mice model.
Vidyadhara J (PhD Scholar) presented the progress of his ongoing PhD work in the area of Parkinson's Disease using an MPTP mice model.
Vidyadhara (PhD Scholar) presented the paper by Tran et al.,entitled "a-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfoldeda-Synuclein and Neurodegeneration" from Cell Reports (2014).
Accumulation of misfolded alpha-synuclein (α-syn) into Lewy bodies (LBs) and Lewy neurites (LNs) is a major hallmark of Parkinson’s disease (PD) and dementia with LBs (DLB). Recent studies showed that synthetic preformed fibrils (pffs) recruit endogenous α-syn and induce LB/LN pathology in vitro and in vivo, thereby implicating propagation and cell-to-cell transmission of pathological α-syn as mechanisms for the progressive spread of LBs/LNs. Here, we demonstrate that α-syn monoclonal antibodies (mAbs) reduce α-syn pff-induced LB/LN formation and rescue synapse/neuron loss in primary neuronal cultures by preventing both pff uptake and subsequent cell-to-cell transmission of pathology. Moreover, intraperitoneal (i.p.) administration of mAb specific for misfolded α-syn into nontransgenic mice injected intrastriatally with α-syn pffs reduces LB/LN pathology, ameliorates substantia nigra dopaminergic neuron loss, and improves motor impairments. We conclude that α-syn antibodies could exert therapeutic effects in PD/DLB by blocking entry of pathological α-syn and/or its propagation in neurons.
Niranjan presented the paper by Lin et al from J Neuroscience 2014 entitled "Loss of PINK1 Attenuates HIF-1 Induction by Preventing 4E-BP1-Dependent Switch in Protein Translation under Hypoxia".
Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.
'Understanding Parkinson's Disease: From Clinics to Basics' - An Educational Programme was organized by the Department of Neurophysiology, at NIMHANS.
This is an educational activity endorsed by International Parkinson and Movement Disorders Society, USA and was open to Basic Scientists as well as Clinicians interested in the study of Parkinson's Disease.
Abhilash PL (PhD Scholar) presented the paper entitled "NADPH Oxidase and Aging Drive Microglial Activation, Oxidative Stress, and Dopaminergic Neurodegeneration Following Systemic LPS Administration" by Qin etal, from Glia 2013.
Parkinson’s disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (THþIR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2þ/þ) mice with NOX subunit gp91phox-deficient (NOX2/) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of THþIR neurons in NOX2þ/þ mice, whereas NOX2/ mice did not show a significant decrease. Microglia (Iba1þIR) showed morphological activation in NOX2þ/þ mice, but not in NOX2/ mice at 1 hr.
Treatment of NOX2þ/þ mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5–6.5-fold increases in NOX2 protein (þIR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFa, IL-1b, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2þ/þ mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of
Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.
H Yarreiphang (Phd Scholar) presented the paper by Zheng etal from PLoS ONE Aug 2013 entitled "Autophagic Impairment Contributes to Systemic Inflammation-Induced Dopaminergic Neuron Loss in the Midbrain"
Background: Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as a-synuclein (a-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown.
Results: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of a-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-a induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-a (50 ng/ml) increased the expression of LC3-II, p62, and a-SYN, implying that TNF-a triggered autophagic impairment in cells.
Conclusion: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaque
Vidhyadara DJ (PhD Scholar) presented a paper by Carlos Barcia and group, titled "Persistent phagocytic characteristics of microglia in the substantia nigra of long-term Parkinsonian macaque", publised in Journal of Neuroimmunology Aug 2013.
Patients with Parkinson's disease show persistent microglial activation in the areas of the brain where the degeneration of dopaminergic neurons takes place. The reason for maintaining this activated state is still unknown, but it is thought that this persistent microglial activation may contribute to the degeneration of dopaminergic neurons. In this study, we report the microanatomical details of microglia and the relationship between microglia and neurons in the substantia nigra pars compacta of Parkinsonian monkeys years after insult with MPTP. We observed that microglial cells appear polarized toward dopaminergic neurons in MPTP-treated macaques compared to untreated animals and present clear phagocytic characteristics, such as engulfing gliaptic contacts, an increase in Golgi apparatus protein machinery and ball-and-chain phagocytic buds. These results demonstrate that activated microglia maintain phagocytic characteristics years after neurotoxin insult, and phagocytosis may be a key contributor to the neurodegenerative process.
Some interesting points from the presentation: