Review: Parkinson's disease: from synaptic loss to connectome dysfunction

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder with prominent loss of nigro-striatal dopaminergic neurons. The resultant dopamine (DA) deficiency underlies the onset of typical motor symptoms (MS). Nonetheless, individuals affected by PD usually show a plethora of nonmotor symptoms (NMS), part of which may precede the onset of motor signs. Besides DA neuron degeneration, a key neuropathological alteration in the PD brain is Lewy pathology. This is characterized by abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates mainly composed of α-synuclein. Lewy pathology has been hypothesized to progress in a stereotypical pattern over the course of PD and α-synuclein mutations and multiplications have been found to cause monogenic forms of the disease, thus raising the question as to whether this protein is pathogenic in this disorder. Findings showing that the majority of α-synuclein aggregates in PD are located at presynapses and this underlies the onset of synaptic and axonal degeneration, coupled to the fact that functional connectivity changes correlate with disease progression, strengthen this idea. Indeed, by altering the proper action of key molecules involved in the control of neurotransmitter release and re-cycling as well as synaptic and structural plasticity, α-synuclein deposition may crucially impair axonal trafficking, resulting in a series of noxious events, whose pressure may inevitably degenerate into neuronal damage and death. Here, we provide a timely overview of the molecular features of synaptic loss in PD and disclose their possible translation into clinical symptoms through functional disconnection.

Changes in functional organization and white matter integrity in the connectome in Parkinson's disease

“…A possible explanation for this nonlinear relationship specifically in PD could be synaptic dysfunction and changes in synaptic plasticity. Growing evidence suggests that neurodegeneration in PD is more likely to start at the synapse (Bellucci et al, 2016, Picconi et al, 2012; Schulz-Schaeffer, 2010). The highest percentage of alpha-synuclein aggregates in PD are localized at the presynapses.…”

The Contribution ofα-Synuclein Spreading to Parkinson’s Disease Synaptopathy

“…The expression of α -synuclein is elevated within the synapses of nigral dopamine neurons [38]. There, the protein can modulate synaptic dopamine release by directly modulating the dopamine transporter (DAT), synapsin III, the small GTP-binding protein Rab3A, and the soluble N-ethylmaleimide sensitive fusion attachment protein receptor (SNARE) protein member vesicle associated membrane protein-2 (VAMP-2) [6]. Indeed, it catalyzes the entry of VAMP-2 into the SNARE complex [39] and enhances DAT localization at the plasma membrane [40], which consistently is impaired by α -synuclein aggregation [41, 42].…”

“…In the last few years, it has become evident that PD may be considered as a synaptopathy [1, 2]. Indeed, striatal dopaminergic terminal loss appears to precede neurodegeneration in the substantia nigra [3, 4] and the deposition of α -synuclein, which is considered as a causative factor for the onset of the disorder, mainly affects synaptic terminals in its early stages [5, 6]. Nonetheless, the exact molecular mechanisms that determine the selective vulnerability of nigrostriatal synapses to α -synuclein deposition are still enigmatic.…”

Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque

“…Irrespective of etiology and varying upstream mechanisms, deposition of alpha-synuclein (aSyn) is a defining pathological feature of PD and is increasingly being understood to be involved in synaptic dysfunction [4–6] and axonal transport deficits [7, 8] and produces ER-Golgi stress [9, 10], to name a few key cell biological processes. Accumulation of aSyn has been found upon postmortem examination in the olfactory bulb, amygdala, nucleus basalis, substantia nigra, locus coeruleus, dorsal motor nucleus of vagus and the cerebral cortex [11, 12].…”