The defining feature of PD is the accumulation of aggregated alpha-synuclein protein in the substantia nigra. The degeneration of dopaminergic neurons in the substantia nigra results in the loss of their connections to the striatum, underlying the degradation of motor function seen in PD (tremor, slow movement, rigidity, gait difficulty). However, aggregated alpha-synuclein also affects other neuronal populations, including serotonergic (raphe), noradrenergic (LC), and cholinergic neuorns (NBM), and each of these neuronal populations has widespread projections to other brain regions.
Our lab has investigated the loss of these projections in PD by measuring the neurotransmitters and proteins specifically produced by the innervating axons from each neuronal population. The results of the analysis are generating a map of the loss of different types of connections (dopaminergic, serotonergic, noradrenergic and cholinergic) within the brain as a result of PD. In future studies, we are examining the relationship of these lost connections to the non-motor symptoms of PD (including impairment of different cognitive domains, changes in mood, hallucinations, and problems with sleep). Understanding these relationships will assist with the development of better treatments for the non-motor symptoms of PD.
- Buddhala, C, Loftin SK, Kuley BM, Cairns NJ, Campbell MC, Perlmutter JS, Kotzbauer PT. (2015). Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. Ann Clin Transl Neurol. 2(10):949-959. PubMed PMID: 26478895.
- Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM. (2008). Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci. 28(30):7687-98. PubMed PMID: 18650345.