Direct visualization of CHIP-mediated degradation of alpha-synuclein in vivo: implications for PD therapeutics.

Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity.

Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not α-synuclein-induced neuronal cell loss.

Hsp90 inhibitors such as geldanamycin potently induce Hsp70 and reduce cytotoxicity due to α-synuclein expression, although their use has been limited due to toxicity, brain permeability, and drug design. We recently described the effects of a novel class of potent, small molecule Hsp90 inhibitors in cells overexpressing α-synuclein. Screening yielded several candidate compounds that significantly reduced α-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction.

Direct detection of alpha synuclein oligomers in vivo.

Background: Rat models of Parkinson's disease are widely used to elucidate the mechanisms underlying disease etiology or to investigate therapeutic approaches. Models were developed using toxins such as MPTP or 6-OHDA to specifically target dopaminergic neurons resulting in acute neuronal loss in the substantia nigra or by using viral vectors to induce the specific and gradual expression of alpha synuclein in the substantia nigra. The detection of alpha- synuclein oligomers, the presumed toxic species, in these models and others has been possible using only indirect biochemical approaches to date.

Abnormal involuntary movement (AIM) expression following D2 dopamine agonist challenge is determined by the nature of prior dopamine receptor stimulation (priming) in 6-hydroxydopamine lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions show sensitization (priming) of rotational behavior upon repeated treatment with dopamine agonists. To relate these observations to dyskinesias exhibited by Parkinson's Disease patients, we assessed abnormal involuntary movements (AIMs) in 6-OHDA rats, which were primed with three injections of either the following: water, D1/D2 agonist apomorphine (Apo) (0.5mg/kg), D1 agonist SKF38393 (SKF) (10mg/kg) or D2 agonist quinpirole (Quin) (1 or 2.