- ASSOCIATE PROFESSOR Neurology
Ph.D., Osmania University
Dystonia and Prkinson's Disease
The focus of our laboratory is to understand the basis of neurological disorders such as Dystonia and Parkinson's disease (PD). Dystonia is a neurological disorder characterized by excessive, involuntary muscle contractions, which can result in twisting movements and abnormal postures, and can cause significant disability. In many cases the cause of dystonia is not known and therapy is sub-optimal and often ineffective. There is strong evidence that basal ganglia abnormalities, in particular the dopaminergic nigrostriatal pathway, which degenerates in PD, play a role in dystonia, but the mechanism remains obscure. Recently a mutation in the DYT1 gene on chromosome 9q34 was linked to one of the most severe types of inherited dystonia known as childhood onset dystonia. The gene encodes for a novel protein termed torsinA, the function of which is not yet known. This mutation, which causes disease in 30-40% of carriers, is a 3-base pair (GAG) deletion resulting in the loss of a glutamic acid residue and can be inherited in an autosomal dominant manner but may also occur sporadically. The role of torsinA in cellular function is not known. However, examination of the amino acid sequence predicted from the cDNA reveals that it has an ATP-binding domain and a nuclear localization sequence. Lewy bodies are the neuropathological hallmark of Parkinson's disease, which is characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta. We have demonstrated the accumulation of torsinA in Lewy bodies in PD and in Dementia with Lewy Bodies. The significance of this finding is unknown, but may implicate torsinA in neuronal dysfunction in PD as well as in dystonia. Using molecular, cell biological, immunocytochemical and protein chemistry techniques we are investigating the cellular and sub-cellular localization, and cellular function of torsinA and its possible dysfunction in these neurological disorders. We have also developed transgenic mouse lines and cell culture model systems which will enable us to further understand the basis of childhood onset dystonia.PUBLICATIONS
1. Shashidharan P., and Plaitakis, A (2014). The Discovery of Human of GLUD2 Glutamate Dehydrogenase and Its Implications for Cell Function in Health and Disease. Neurochem Res. Neurochem Res. 39(3):460-70.
2. Armata IA, Diplas A, Ozelius LJ and Shashidharan P (2012) Allelic Imbalance in TOR1A mRNA Expression in Manifesting and Non-Manifesting Carriers of the GAG-Deletion," Journal of Nucleic Acids, vol. 2012, Article ID 985260.doi:10.1155/2012/985260.
3. Nambu A, Chiken S, Shashidharan P, Nishibayashi H, Ogura M, Kakishita K, Tanaka S, Tachibana Y, Kita H, ItakuraT (2011). Reduced pallidal output causes dystonia. Frontiers in System Neuroscience. 5, 89.
4. Lange N, M Hamann, P. Shashidharan, A Richter (2011) Behavioural and pharmacological examinations in a transgenic mouse model of early-onset torsion dystonia. Pharmacology, Biochemistry and Behavior 97(4):647-655.
5. Giannakopoulou D, IA Armata, A Mitsacos, P. Shashidharan, P. Giompres. (2010) Modulation of the basal ganglia dopaminergic system in a transgenic mouse exhibiting dystonia-like features. J Neur. Trans.117(12):1401-1409.
6. Bao, L., J. C. Patel, R. H. Walker, P. Shashidharan and M. E. Rice (2010). "Dysregulation of striatal dopamine release in a mouse model of dystonia." J Neurochem 114(6): 1781-91.
7. Holton, J. L., S. A. Schneider, T. Ganesharajah, S. Gandhi, C. Strand, P. Shashidharan, J. Barreto, N. W. Wood, A. J. Lees, K. P. Bhatia and T. Revesz (2008). "Neuropathology of primary adult-onset dystonia." Neurology 70(9): 695-9.
8. Chiken, S., P. Shashidharan and A. Nambu (2008). "Cortically evoked long-lasting inhibition of pallidal neurons in a transgenic mouse model of dystonia." J Neurosci 28(51): 13967-77.
9. Armata, I. A., M. Ananthanarayanan, N. Balasubramaniyan and P. Shashidharan (2008). "Regulation of DYT1 gene expression by the Ets family of transcription factors." J Neurochem 106(3): 1052-65.
10. Shashidharan, P., D. Sandu, U. Potla, I. A. Armata, R. H. Walker, K. S. McNaught, D. Weisz, T. Sreenath, M. F. Brin and C. W. Olanow (2005). "Transgenic mouse model of early-onset DYT1 dystonia." Hum Mol Genet 14(1): 125-33.
Armata IA, Diplas AI, Ozelius LJ, Shashidharan P. Allelic Imbalance in TOR1A mRNA Expression in Manifesting and Non-Manifesting Carriers of the GAG-Deletion. Journal of nucleic acids 2012; 2012.
Shashidharan P, Plaitakis A. The Discovery of Human of GLUD2 Glutamate Dehydrogenase and Its Implications for Cell Function in Health and Disease. Neurochemical research 2014 Mar; 39(3).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Below are financial relationships with industry reported by Dr. Shashidharan during 2012 and/or 2013. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
- Life Technologies Corporation
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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