| First Author | Farrell KF | Year | 2014 |
| Journal | J Neurochem | Volume | 128 |
| Issue | 4 | Pages | 536-46 |
| PubMed ID | 24117685 | Mgi Jnum | J:206612 |
| Mgi Id | MGI:5551555 | Doi | 10.1111/jnc.12481 |
| Citation | Farrell KF, et al. (2014) Non-motor parkinsonian pathology in aging A53T alpha-Synuclein mice is associated with progressive synucleinopathy and altered enzymatic function. J Neurochem 128(4):536-46 |
| abstractText | Aging, the main risk factor for Parkinson's disease (PD), is associated with increased alpha-synuclein levels in substantia nigra pars compacta (SNc). Excess alpha-synuclein spurs Lewy-like pathology and dysregulates the activity of protein phosphatase 2A (PP2A). PP2A dephosphorylates many neuroproteins, including the catecholamine rate-limiting enzyme, tyrosine hydroxylase (TH). A loss of nigral dopaminergic neurons induces PD movement problems, but before those abnormalities occur, behaviors such as olfactory loss, anxiety, and constipation often manifest. Identifying mouse models with early PD behavioral changes could provide a model in which to test emerging therapeutic compounds. To this end, we evaluated mice expressing A53T mutant human (A53T) alpha-synuclein for behavior and alpha-synuclein pathology in olfactory bulb, adrenal gland, and gut. Aging A53T mice exhibited olfactory loss and anxiety that paralleled olfactory and adrenal alpha-synuclein aggregation. PP2A activity was also diminished in olfactory and adrenal tissues harboring insoluble alpha-synuclein. Low adrenal PP2A activity co-occurred with TH hyperactivity, making this the first study to link adrenal synucleinopathy to anxiety and catecholamine dysregulation. Aggregated A53T alpha-synuclein recombinant protein also had impaired stimulatory effects on soluble recombinant PP2A. Collectively, the data identify an excellent model in which to screen compounds for their ability to block the spread of alpha-synuclein pathology associated with pre-motor stages of PD. Aging A53T alpha-synuclein mice develop behaviors common to premotor Parkinson's disease (PD) with synucleinopathy occuring in adrenal gland, olfactory bulb, and intestine. Insoluble aggregated A53T alpha-synuclein loses PP2A-stimulatory-effects, which normally down regulate dopamine synthesis. This is the first study to link adrenal synucleinopathy to catecholamine dysregulation and anxiety. The mice are an excellent model for testing emerging neuroprotective therapies for PD. |
