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).
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). Abhilash Parli (2nd yr PhD Scholar) presented his seminar titled "Microglia: Guardians of the Brain''.
He outlined his talk under the following headings:
The talk was thought provoking and brought in healthy discussions. 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.
ABSTRACT 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 age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age. Pooja Shri Mishra (PhD Scholar) presented the paper by Kang etal from Nature Neuroscience March 2013 entitled "Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis"
ABSTRACT Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2+ cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset. Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes. Abhilash PL (1st year PhD scholar) presented his seminar on "Astrocytes in neurodegenerative diseases".
After a brief introduction of the morphology and classification of astrocytes (broadly protoplasmic - with short 30 micron processes and fibrous with 300 micron long processes), Abhilash went over the GFAP (expressed more during reactive astrogliosis) and S100Beta (Ca binding protein that gets expressed more during injury) expression and then came to the various functional roles of astrocytes. Astrocytes have a significant role in the lifespan of synapse formation (from birth to death of synapes) and interestingly, under healthy conditions they maintain own territorial domains with less than 5% of overlap between astrocyte processes. Through the astrocytic gap junctions, K+ buffering and Ca+ wave propogation take place. In the tripartite synapse, only 20% of the glutamate released is taken up by the postsynaptic terminal with 80% of it being cleared up by astrocytes. Astrocytes are also involved in Glutathione synthesis and produce precursers that allow neurons to also manufacture Glutathione (as they can't take in Glutathione from extracellular space). Astrocytes are implicated in neurodegenerative diseases such as ALS (can serve as an early marker for some SOD mutant mice models as reactive astrogliosis is observed at 5 weeks while motor neuron loss is seen only at 15 weeks),Alzheimers and Parkinsons Disease(astrocytes can secrete MPTP like toxins. Microglia could be causative for astrogliosis). Rukmani (1st year MPhil Scholar) presented the paper by Kim JY etal 2012 from World Journal of Stem Cells entitled: "Umbilical cord blood mesenchymal stem cells protect amyloid-β42 neurotoxicity via paracrine".
ABSTRACT AIM: To understand the neuroprotective mechanism of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) against amyloid-β42 (Aβ42) exposed rat primary neurons. METHODS: To evaluate the neuroprotective effffect of hUCB-MSCs, the cells were co-cultured with Aβ42-exposed rat primary neuronal cells in a Transwell apparatus. To assess the involvement of soluble factors released from hUCB-MSCs in neuroprotection, an antibody-based array using co-cultured media was conducted. The neuroprotective roles of the identified hUCB-MSC proteins was assessed by treating recombinant proteins or specific small interfering RNAs (siRNAs) for each candidate protein in a co-culture system. RESULTS: The hUCB-MSCs secreted elevated levels of decorin and progranulin when co-cultured with rat primary neuronal cells exposed to Aβ42. Treatment with recombinant decorin and progranulin protected from Aβ42-neurotoxicity in vitro. In addition, siRNA-mediated knock-down of decorin and progranulin production in hUCB-MSCs reduced the anti-apoptotic effffects of hUCB-MSC in the co-culture system. CONCLUSION: Decorin and progranulin may be involved in anti-apoptotic activity of hUCB-MSCs exposed to Aβ42. Poojashri Mishra (3rd year PhD scholar) presented a seminar on Neurodegeneration and carbohydrates. She explored the Hexose biosynthesis pathways and the role of nutrients in pro-survival and pro-growth activity.
Glycosylation (and O-GlcNac) is involved in formation of vesicular proteins, in the nucleolus (both transcriptional and translational activity), and with tau proteins, neurofilaments and tubulins. GlcNac is implicated in Type II diabetes and seems to be reduced in Cancer and Neurodegenerative diseases such as MS, ALS etc. Glucosamine seems to inhibit Lipopolysaccharides (that activate microglia). Glucosamine injection given in the peri-infarct period (1 hr pre to 3 hr post) seems to be neuroprotective. Shruti S (2nd year PhD scholar) presented the paper "Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis" by Bernadett Kalmar, Emem Edet-Amana & Linda Greensmith from the journal Amyotrophic Lateral Sclerosis, 2012.
ABSTRACT We undertook a longitudinal study of the histological and biochemical changes at the neuromuscular junction (NMJ) in muscles of SOD1-G93A mice. We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol. Tissue samples of treated and untreated mSOD mice were analysed for AChE and ChAT enzyme activities as markers of neuromuscular function. Sections of hindlimb muscles (TA, EDL and soleus) were also stained for succinate dehydrogenase and silver cholinesterase activities as well as for immunohistochemistry. Hsp70 levels were also measured from muscle samples using ELISA. Results showed that denervation and nerve sprouting were present at symptom onset in fast muscles, although slow muscles remained fully innervated. Cholinergic enzyme activities were reduced prior to denervation and declined further with disease progression. Reduction of endplate size, a slow to fast shift in muscle phenotype was also observed. Treatment with arimoclomol delayed the appearance of these changes, increased innervation, cholinergic enzyme activities and endplate size and reversed muscle fi bre transformation. These beneficial effects of arimoclomol in muscles were accompanied by an increase in Hsp70 expression. In conclusion, our results indicate that pharmacological targeting of muscles at early stages of disease may be a successful strategy to ameliorate disease progression in ALS. Shilpa BM (3rd year PhD Scholar) presented her seminar of "Enriched Environment and recovery of Brain functions".
A number of studies suggest that enriched environments ameliorate the effects of traumatic brain injury; neurodevelopment and ageing; neurodegenerative diseases such as Alzheimers and Huntington's; depression, fear and stress; addictions; epilepsy... and seem to function via increase of cognitive reserve. Benefits include increase in synaptic density, neurotrophic support, glial proliferation, neurogenesis, vasculature support. Several studies have been done in our labs (Subicular lesion studies by Anandh and Bindu B; Restraint stress by Ramkumar and Veena; Fear conditioning by Preethi; Depression by Mahati and now on Epilepsy as well). Dr Aparna Sharma (Research Associate) presented her concept seminar on "Are organotypic 3D cell culture models more suitable for the study of neuro degenerative diseases?"
Aparna started with an overview of the historical development of cell culture models. Tissue Cultures in Petri Dishes (in 2D layers) was started off by Wilhelm Roux in 1885. The field has moved onto organotypic slice models where tissue slices were grown and more recently onto 3D cultures where 3D scaffolds (10-30 micrometers) are provided for the cells to grow. Aparna cited a number of studies where 3D culture models with different types of scaffolds have been compared with the traditional 2D cell culture approaches. The 3D culture approach seems to be better for a number of reasons:
A number of 3D scaffolds are now commercially available - ranging from the natural Aragonite (bio-active, derived from the highly porous coral exoskeleton, made up of Calcium Carbonate and functions as a calcium supplement), Hydrogel (synthetic and used for neuronal cells), Human ECM (contains collagens, laminins etc) and PuraMatrix (considered to be self-assembling). Given the number and range of benefits accrued, Aparna concluded that organotypic 3D cell culture models are valuable for the study of neurodegenerative diseases. |
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