Molecular mechanisms of Parkinson's Disease
Parkinson's Disease (PD) is the second most common progressive neurodegenerative disorder, affecting 1-2% of all individuals above the age of 65. PD is characterized by muscle rigidity, resting tremor, bradykinesia and gait disturbance with dysequilibrium. The neuropathological hallmark in post mortem brains is the selective degeneration of specific subsets of mesencephalic dopaminergic (DA) cells and the formation of cytoplasmic aggregates called Lewy Bodies (LB). The loss of DA synapses in the striatum is believed to be the primary cause for disruption of the ability to control movements.
(i) We are applying functional genomics techniques to study gene expression profiles in cellular and animal models of the disease. Since in PD the control of movements is altered for the selective loss of a subset of dopaminergic cell groups, we are studying gene expression in the mesencephalic dopaminergic cell system to correlate gene clusters to cell’s susceptibility.
(ii) We are studying alpha-synuclein (AS) and DJ-1, two proteins encoded by genes associated with rare forms of early-onset familial PD.
The role of AS in PD has been confirmed by its localization in the Lewy bodies, fibrillar intracytoplasmic inclusions that are the histopathological hallmark of PD. It is believed that inhibition of AS activity or expression may be a valid approach to develop new therapeutics for PD. In collaboration with P. Carloni, SISSA, Italy, we are investigating dopamine-binding to AS. The model is validated by mutational analysis performed in collaboration with Dr. Lashuel Hilal at EPH, Lausanne, Suisse. Mutations in the PARK7/DJ-1 gene were found to be associated with autosomal recessive early-onset PD. DJ-1 is involved in oxidative stress response exerting a pro-survival role. It is unclear how PD-linked mutations alter DJ-1 structure and function and which biochemical activity is important for its neuro-protective action.
In collaboration with P. Carloni, SISSA, Italy, we apply computational models to unveil the structural basis for DJ-1 loss of function. The effects of mutations for DJ-1 structure are investigated in reduced and oxidized states using molecular dynamics simulations.
In collaboration with G. Del Sal, CIB, Trieste, Italy, we have isolated a group of DJ-1 interactors in a yeast two-hybrids screening. We are currently focusing our attention on TTRAP (TRAF and TNF receptor associated protein). TTRAP may act both as a transcriptional regulator and as an endonuclease, sharing significant structural homology and biochemical activity with APE1/Ref-1, a major player in cellular oxidative stress response.
In collaboration with G. Tell, Universita’ di Udine, Italy, we are currently analyzing its role in DNA repair.
