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Synaptic Protein Alterations in Parkinson’s Disease

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Abstract

Alterations occur within distal neuronal compartments, including axons and synapses, during the course of neurodegenerative diseases such as Parkinson’s disease (PD). These changes could hold important implications for the functioning of neural networks, especially since research studies have shown a loss of dendritic spines locating to medium spiny projection neurons and impaired axonal transport in PD-affected brains. However, despite ever-increasing awareness of the vulnerability of synapses and axons, inadequate understanding of the independent mechanisms regulating non-somatic neurodegeneration prevails. This has resulted in limited therapeutic strategies capable of targeting these distinct cellular compartments. Deregulated protein synthesis, folding and degrading proteins, and protein quality-control systems have repeatedly been linked with morphological and functional alterations of synapses in the PD-affected brains. Here, we review current understanding concerning the proteins involved in structural and functional changes that affect synaptic contact-points in PD. The collection of studies discussed emphasizes the need for developing therapeutics aimed at deregulated protein synthesis and degradation pathways operating at axonal and dendritic synapses for preserving “normal” circuitry and function, for as long as possible.

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Abbreviations

ACh:

Acetylcholine

SNCA [gene]:

α-Synuclein

αSYN [protein]:

α-Synuclein

BACE1:

β-Site amyloid precursor cleaving enzyme

ßSYN [protein]:

ß-Synuclein

AD:

Alzheimer’s disease

Aß:

Amyloid-ß

APP:

Amyloid precursor protein

CSPα:

Cysteine-string protein α

DLBD:

Diffuse Lewy body disease

DA:

Dopamine

EF1A:

Elongation factor 1-alpha

FRET:

Förster resonance energy transfer

GST:

Glutathione S-transferase

Hsp:

Heat shock protein

LBs:

Lewy bodies

LRRK2:

Leucine-rich repeat kinase 2

LRP1:

Lipoprotein receptor-related protein 1

LC-MS/MS:

Liquid chromatography tandem mass spectrometry

MEF2:

Myocyte enhancer factor 2

MSNs:

Medium spiny neurones

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NSF:

N-ethylmaleimide sensitive factor

PINK1:

Phosphatase and tensin homologue-induced kinase1

PolyQ:

Polyglutamine

PKC:

Putative protein kinase C

5-HT:

Serotonin

6-OHDA:

6-Hydroxydopamine

PrP:

Prion protein

5-HT:

Serotonin

SN:

Substantia nigra

UCH-L1:

Ubiquitin carboxyl terminal hydrolase-L1

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This work was supported by the UK Medical Research Council.

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  1. Institute for Ageing and Health, Department of Neurology, The University of Newcastle, Newcastle-Upon-Tyne, UK

    Ilse S. Pienaar, David Burn & Christopher Morris

  2. Parkinson’s Disease Research Group, Centre for Neuroscience, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK

    David Dexter

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  1. Ilse S. Pienaar
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Correspondence to Ilse S. Pienaar.

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Pienaar, I.S., Burn, D., Morris, C. et al. Synaptic Protein Alterations in Parkinson’s Disease. Mol Neurobiol 45, 126–143 (2012). https://doi.org/10.1007/s12035-011-8226-9

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