Interactions of Protein Aggregation in Parkinson's Disease with Dementia
|2010 Progress Report Update|
|Benoit Giasson, PhD
Project 4 focuses on the relationship between abnormal protein aggregation and the spectrum of clinical impairments in Parkinson's disease (PD) and Parkinson's disease with dementia (PDD) and investigates the molecular mechanisms that produce alpha-synculein and tau inclusions in PD, Parkinson's disease with dementia and/or Dementia with Lewy Bodies (PDD/DLB), and Lewy Body Variant of Alzheimer's disease (LBVAD). Additionally, this project assesses new directions in molecular therapies for neurodegeneration and dementia.
Despite the knowledge that the demise of specific neuronal populations is responsible for some clinical features in PD, there are significant unknowns about the mechanisms that lead to neuronal dysfunction and death; protein aggregation may play a significant role. Although familial PD is relatively rare, the identification of mutations in the alpha-synuclein gene has lead to the discovery that this protein is the major component of disease-characteristic inclusions known as Lewy Bodies (LBs) and Lewy Neuritis (LNs). Alpha-synuclein is normally a soluble protein, but it can polymerize into ~10-15 nm fibrils with specific biophysical properties known as "amyloid" to form these pathological inclusions. The pathological amyloidogenic inclusions diagnostic of AD, i.e. neurofibrillary tangles comprised of tau protein and A-beta peptide deposits in senile plaques frequently occur with alpha-synuclein pathologies. It has been shown that alpha-synuclein is able to act as an inducer of tau aggregation, and both proteins can enhance the polymerization of each other once this process is initiated.
It is hypothesized that specific molecular interactions are involved in this process. It is also proposed that aberrant physiological alterations, such as nitrative damage and hyperphosphorylation, may promote alpha-synuclein and tau interactions. These mechanisms are studied and tested in vitro by studying effects on filament formation. Using TG mice that express human alpha-synuclein and tau, the notion that minute amounts of alpha-synuclein may induce tau polymerization in vivo without leaving overt deposits of alpha-synuclein will be tested. These studies will also assess selective neuronal vulnerability and specific behavioral impairments, reminiscent of human diseases that may result from alpha-synuclein and tau interactions leading to the formation of inclusions.
In addition, TG mouse models of A-beta peptide deposits will be used to ascertain the hypothesis that these inclusions may initiate pathological events that can promote alpha-synuclein aggregation. These findings provide important information on mechanisms and physiological changes that lead to the formation of alpha-synuclein and tau inclusions, and may lead to insights in planning for effective therapeutic approaches for PD and related neurodegenerative diseases.
We expect that findings from this past funding year will provide important insights into the mechanisms and the pathological significance of the interactions of three distinct amyloidogenic proteins (alpha-synuclein, tau and Ab peptide) that are involved in PD, PDD and related diseases. These findings may further define pathways of aberrant brain protein aggregation that culminate in neuronal damage. Importantly, these findings may provide an even more compelling rationale for pursuing efforts to identify therapeutic agents that could directly or indirectly inhibit the formation of amyloid in brain.
- Waxman, E.A., Covy, J.P., Bukh, I., Li, X., Dawson, T.M., Giasson B.I. Overexpression of leucine-rich repeat kinase 2 leads to aggresome-like formation, but it is not associated with α-synuclein aggregation or pathological inclusions. J. Neuropath. Exp. Neurol. 68, 785-96, 2009. PMC2722758
- Waxman, E.A., Mazzulli, J.R., Giasson, B.I. Characterization of hydrophobic residue requirements for α-synuclein fibrillization. Biochemistry, 48, 9427-9436, 2009. PMC2758333
- Waxman, E.A., Emmer, K.L., Giasson, B.I. Residues Glu83 plays a major role in negatively regulating α-synuclein amyloid formation. Biochem. Biophys. Res. Commun. 391, 1415-1420, 2010. PMC2812690
- Giasson BI, Covy J, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin V. Biochemical and pathological characterization of LRRK2. Ann Neurol, 59:315-322, 2006.
- Mazzulli JR, Mishizen AJ, Giasson BI, Lynch DR, Thomas SA, Nakashima A, Nagatsu T, Ota A, Ischiropoulos H. Cytosolic catechols inhibit alpha-synuclein aggregation and facilitate the formation of intracellular soluble oligomeric intermediates. J Neurosci, 26:10068-10078, 2006.
- Ramsey CP, Giasson BI. Role of mitochondrial dysfunction in Parkinson's disease: Implications for treatment. Drugs Aging, 24:95-105, 2007.