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Review
. 2014:2014:289728.
doi: 10.1155/2014/289728. Epub 2014 Sep 16.

Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms

Valérie Drouet  1 , Suzanne Lesage  2
Affiliations
Review

Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms

Valérie Drouet et al. Biomed Res Int. 2014.

Abstract

Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase highly expressed in nerve terminals. Its two phosphatase domains dephosphorylate phosphoinositides present in membranes, while its proline-rich domain directs protein-protein interactions with synaptic components, leading to efficient recycling of synaptic vesicles in neurons. Triplication of SYNJ1 in Down's syndrome is responsible for higher level of phosphoinositides, enlarged endosomes, and learning deficits. SYNJ1 downregulation in Alzheimer's disease models is protective towards amyloid-beta peptide (Aβ) toxicity. One missense mutation in one of SYNJ1 functional domains was recently incriminated in an autosomal recessive form of early-onset Parkinson's disease (PD). In the third decade of life, these patients develop progressive Parkinsonism with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia. The identification of this new gene, together with the fact that most of the known PD proteins play a role in synaptic vesicle recycling and lipid metabolism, points out that synaptic maintenance is a key player in PD pathological mechanisms. Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder.

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Figures

Figure 1
Figure 1
Functional and interaction domains of the two major isoforms of SYNJ1. The 145 kDa (top) and the 170 kDa (bottom) SYNJ1 isoforms harbor two functional inositol phosphatase domains, an N-terminal Sac1 domain and a more central 5′-phosphatase domain. Several protein-protein interaction domains are found in the C-terminal part of the proteins: one or two PRD domains, AP2 binding motifs (WxxF, FxDxF, and DxF, in pink), and Eps15 binding motifs (NPF: asparagine-proline-phenylalanine, in blue). The homozygous mutation Arg258Gln, found in Parkinson's disease patients, is indicated in red. Numbers indicate the amino acid positions along the proteins. Sac1: suppressor of actin1; PRD: proline-rich domain; AP2: adaptor protein complex 2; Eps15: epidermal growth factor receptor pathway substrate 15.
Figure 2
Figure 2
Synaptic vesicle recycling and PD genes. Schematic representation of a presynaptic terminal showing the PD genes (red boxes) and their role in synaptic vesicle recycling. (a) During endocytosis, invagination of the clathrin-coated membrane requires endophilin. Endophilin harbors several SH3 domains, which can interact with SYNJ1 PRD domain and/or parkin. (b) LRRK2 phosphorylates endophilin leading to dissociation of the later from clathrin-coated vesicles. (c) Once recruited to the coated vesicles through endophilin, SYNJ1 dephosphorylates PI4,5P into PI, shedding clathrin and its adaptor from the bilayer. (d) Uncoating of the vesicles also requires auxilin intervention and subsequent chaperoning of clathrin molecules. Then, the postendocytic vesicles can return to the reserve pool, where they undergo clustering, or return directly to the release site and enter in an exocytosis step. (e) Synaptic vesicles are docked and then fused to the membrane by means of a multiprotein complex including synaptobrevin and αSYN. (f) PTEN is a lipid phosphatase, which is inhibited by DJ-1, and can increase levels of the mitochondrial PINK1 protein. This pathway is involved in NMDA receptor signaling. (g) Proper mitochondrial functioning leads to ATP synthesis, necessary to mobilize the reserve pool of vesicles during synapse stimulation. PI4,5P: phosphatidylinositol 4,5-bisphosphates; PI: phosphatidylinositol; ATP: adenosine triphosphate; SYNJ1: synaptojanin 1; LRRK2: leucine-rich repeat serine/threonine-protein kinase 2; PTEN: phosphatase and tensin homologue; PINK1: PTEN induced putative kinase 1; DJ-1: Parkinson's disease protein 7; αSYN: alpha-synuclein.
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