Naturally occurring autoantibodies against α-synuclein rescues memory and motor deficits and attenuates α-synuclein pathology in mouse model of Parkinson's disease (original) (raw)

POTENTIAL CONTRIBUTION OF ΑLPHA-SYNUCLEIN DYSREGULATION TO PARKINSON'S DISEASE PATHOLOGY

The motor symptoms of Parkinson's disease (PD) arise after a marked loss of substantia nigra dopaminergic neurons. Common to the surviving nigral neurons in PD brain are proteinaceous aggregates known as Lewy bodies, which contain high levels of the presynaptic protein α-synuclein. Despite being strongly implicated in PD, the precise role of α-synuclein in PD neuropathology remains inconclusive. However, it is known that the α-synuclein protein contributes to the normal functioning of dopaminergic neurons in part by interacting with a number of key regulatory proteins and other cellular components. Normally, α-synuclein is present at low levels and in a soluble form that can interact with proteins to modulate their functions, especially those that regulate dopamine production, release, and reuptake. In aging human brain, α-synuclein levels rise, which triggers over-modulation of α-synuclein interacting proteins. Eventually, high levels of α-synuclein lead to: (i) Lewy body pathology, (ii) α-synuclein accumulation in insoluble oligomers that impairs its normal regulatory functions, (iii) dysregulation of dopaminergic cellular function, (iv) the death of nigral dopaminergic neurons, and (v) the emergence of PD motor symptoms. This commentary will describe normal functions of α-synuclein in dopaminergic neurons, and explore how changes in the levels and solubility of intraneuronal α-synuclein may contribute to PD.