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UCH‐L1 as a Susceptibility Factor for Nigrostriatal and Mesolimbic Dopamine Neurons: Neurotoxicant Exposure and Aging
Author(s) -
Winner Brittany Michele,
Zhang Harue,
Lookingland Keith,
Goudreau John
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1061.5
Subject(s) - dopamine , substantia nigra , neuroscience , mptp , biology , nigrostriatal pathway , dopaminergic , striatum , proteasome , ubiquitin , deubiquitinating enzyme , parkinson's disease , microbiology and biotechnology , medicine , genetics , disease , gene
Parkinson disease (PD) is a debilitating neurodegenerative disorder in which nigrostriatal (NSDA) dopamine neurons die, affecting signaling within the basal ganglia pathway. Loss of dopamine input to the striatum (ST) results in the motor symptoms required to diagnose PD. Although the majority of cases are idiopathic, genes mutated in familial PD can provide clues to highlight important pathways important in pathogenesis and progression of PD. One such pathway is the ubiquitin proteasome system (UPS) which degrades proteins tagged with ubiquitin (Ub) chains. Since accumulation and aggregation of misfolded proteins such as alpha synuclein is a hallmark of PD, enhancing degradation of key substrates is a lucrative target for therapy. One UPS‐related protein mutated in familial PD is UCH‐L1, a deubiquitinating enzyme responsible for maintaining available pools of free monomeric Ub. UCH‐L1 is an abundant neuron‐specific protein that is critical for normal synaptic function and to maintain the structure of the neuromuscular junction. In a mouse model of oxidative damage specific to dopamine neurons, systemic administration of neurotoxicant MPTP resulted in loss of UCH‐L1 expression and function in the substantia nigra after 24 h. Since loss of UCH‐L1 and loss of phenotypic markers both occur concurrently in NSDA neurons, we hypothesized that loss of UCH‐L1 contributes to susceptibility to neurotoxicant administration. Not all dopamine neurons are equally susceptible in PD: mesolimbic dopamine neurons (MLDA) are spared while NSDA neurons degenerate. We compared NSDA to MLDA neurons and found that MLDA neurons are less susceptible to MPTP‐induced loss of ST dopamine and tyrosine hydroxylase (TH), which coincides with maintenance of UCH‐L1 expression in the ventral tegmental area. In addition, we performed an aging study to determine if UCH‐L1 is lost in aged mice versus young mice and if aged mice are more sensitive to loss of UCH‐L1 after MPTP. Finally, we hypothesized that overexpression of UCH‐L1 in NSDA neurons via rAAV 2/5 will be protective against proteasome impairment and loss of dopamine phenotypic markers after MPTP. Preliminary results indicate that aged mice are more sensitive to MPTP‐induced loss of dopamine in the ST compared to young mice, but not more sensitive to loss of TH and dopamine transporter expression. However, aged mice show decreased metabolism of dopamine as evidenced by lower levels of one of its metabolites, DOPAC. Aged mice also show similar levels of UPS impairment compared to young mice. Further study will determine if UCH‐L1 expression is influenced by aging in NSDA neurons, and if UCH‐L1 overexpression rescues UPS impairment in young mice. Support or Funding Information Institute for Integrative Toxicology T32 Predoctoral Fellowship National Institutes of Health NINDS