Pullanipally Shashidharan

Research

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.

Cover picture showing torsinA expression (shown in green) in pyramidal neurons of human cortex. The GFAP immunoreactivity in astrocytes is shown in red. Shashidharan P, Kramer BC, Walker RH, Olanow CW and Brin MF 2000). Immunohistochemical localization and distribution of torsinA in normal human and rat brain. Brain Res. 853: 197-206.

PUBLICATIONS

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. Torres, G. E., A. L. Sweeney, J. M. Beaulieu, P. Shashidharan and M. G. Caron (2004). "Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia- associated DeltaE-torsinA mutant." Proc Natl Acad Sci U S A 101(44):  15650-5.

9. Shashidharan, P., N. Paris, D. Sandu, L. Karthikeyan, K. S. McNaught, R. H. Walker and C. W. Olanow (2004). "Overexpression of torsinA in PC12 cells protects against toxicity." J Neurochem 88(4):  1019-25.

10. Mytilineou, C., K. S. McNaught, P. Shashidharan, J. Yabut, R. J.  Baptiste, A. Parnandi and C. W. Olanow (2004). "Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress." J Neural Transm 111(10-11): 1237-51.

11. McNaught, K. S., A. Kapustin, T. Jackson, T. A. Jengelley, R.  Jnobaptiste, P. Shashidharan, D. P. Perl, P. Pasik and C. W. Olanow (2004). "Brainstem pathology in DYT1 primary torsion dystonia." Ann Neurol 56(4): 540-7.

12. Walker, R. H., P. F. Good and P. Shashidharan (2003). "TorsinA immunoreactivity in inclusion bodies in trinucleotide repeat diseases." Mov Disord 18(9): 1041-4.

13. Walker, R. H., S. Morgello, B. Davidoff-Feldman, A. Melnick, M. J.  Walsh, P. Shashidharan and M. F. Brin (2002). "Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions." Neurology 58(7): 1031-7.

14. Walker, R. H., M. F. Brin, D. Sandu, P. F. Good and P. Shashidharan (2002). "TorsinA immunoreactivity in brains of patients with DYT1 and non-DYT1 dystonia." Neurology 58(1): 120-4.

15. McNaught, K. S., P. Shashidharan, D. P. Perl, P. Jenner and C. W. Olanow (2002). "Aggresome-related biogenesis of Lewy bodies." Eur J Neurosci 16(11): 2136-48.