Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

Stefanie Smolders; Christine Van Broeckhoven

doi:10.1186/s40478-020-00935-4

Table 1 Genes implicated in Parkinson disease and atypical parkinsonian syndromes

From: Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson’s disease pathogenesis

Gene	MOI	Mutation spectrum	Mutation mechanism	Clinical phenotype	Levodopa response	Pathology	Protein product	Pathway	References
ATP10B	AR	Missense and splice site mutations	LOF	EOPD/LOPD	Limited, levodopa-induced dyskinesia	Unknown	Phospholipid transporting ATPase 10B	Endo-lysosome	[213]
ATP13A2	AR	Missense and PTC mutations	LOF	Juvenile APS called Kufor-Rakeb syndrome with pyramidal signs, supranuclear gaze palsy and cognitive impairment; NCL; HSP	Good	Lipofuscinosis	Cation transporting ATPase 13A2	Endo-lysosome	[37, 90, 257, 277]
ATP6AP2	XR	p.Ser115Ser and p.Asp107Asp	LOF	Juvenile APS with slow disease progression and considerable phenotypic variability including spasticity, intellectual disability and epilepsy	Limited, levodopa-induced dyskinesia	LB-, tau+^b	Renin/prorenin receptor	Endo-lysosome	[176, 279]
DJ-1	AR	Deletions, PTC and missense mutations	LOF	EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment	Limited, levodopa-induced dyskinesia	LB + ^b	DJ-1	Mitochondria	[3, 31, 163, 334].
DNAJC6	AR	c.802-2A > G, p.Thr741Thr, p.Gln791^b, p.Gln846^b, p.Arg927Gly	LOF	Juvenile and early-onset APS with rapidly disease progression and possible intellectual disability, seizures and pyramidal signs.	Limited, levodopa-induced dyskinesia and psychiatric features	Unknown	Auxilin	Vesicular transport	[85, 175, 240]
FBXO7	AR	PTC and missense mutations	LOF	Ranging from classic EOPD to juvenile APS with pyramidal signs (spasticity, impaired fine movements and increased reflexes)	Limited, levodopa-induced dyskinesia and psychiatric features	Unknown	F-box protein 7	Mitochondria	[76, 125, 149, 204, 311, 369]
PARK2	AR	Deletions, PTC and missense mutations	LOF	EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment	Limited, levodopa-induced dyskinesia	Most LB-	Parkin	Mitochondria	[1, 156, 160, 264]
PINK1	AR	Deletions, PTC and missense mutations	LOF	EOPD with slow disease progression and rarely autonomic dysfunctions or cognitive impairment	Limited, levodopa-induced dyskinesia	LB + ^b	PTEN-induced kinase 1	Mitochondria	[156, 293]
PLA2G6	AR	CNV, PTC and missense mutations	LOF	Early-onset APS called dystonia-parkinsonism with cognitive decline, autonomic dysfunction and psychiatric manifestations; INAD; atypical NAD	Limited, levodopa-induced dyskinesia	Axonal spheroid, iron deposits	Phospholipase A2	Endo-lysosome	[126, 139, 157, 161, 184, 249, 316, 370]
LRRK2	AD	Missense mutations	GOF	LOPD with slow disease progression and rarely cognitive impairment	Good	Most LB+, rarely tau+	Leucine-rich repeat kinase 2	Vesicular transport	[132, 251, 285, 346, 379]
SNCA	AD	Multiplications, p.Ala30Pro, p.Glu46Lys, p.Gly51Asp, p.Ala53Glu and p.Ala53Thr^a	GOF	EOPD/LOPD with severe, rapidly disease progression and cognitive impairment; DLB; MSA	Good	LB+	α-Synuclein	Vesicular transport	[6, 28, 162, 181, 191, 263, 272, 284, 295, 317, 372]
SYNJ1	AR	p.Arg258Gln, p.Arg459Pro	LOF	Juvenile APS with possible cognitive impairment, epilepsy and dystonia	Limited, levodopa-induced dyskinesia	LB-, tau+^b	Synaptojanin 1	Vesicular transport	[168, 180, 239, 273]
VPS13C	AR	Deletions and PTC mutations	LOF	EOPD/DLB with severe, rapidly disease progression and cognitive decline	Good	LB+	Vacuolar protein sorting 13C	Endo-lysosome	[69, 183, 193, 297]
VPS35	AD	p.Asp620Asn	LOF	LOPD with slow disease progression and rarely cognitive impairment or neuropsychiatric symptoms	Good	Unknown	Vacuolar protein sorting 35	Vesicular transport	[275, 364]

^aPathogenicity of the SNCA p.His50Gln is uncertain [28]. ^bNeuropathological report of a single carrier. Abbreviations: MOI, mode of inheritance; AR autosomal recessive, AD autosomal dominant, XR X-linked recessive, EOPD early-onset Parkinson disease; LOPD, late-onset Parkinson disease, APS atypical parkinsonian syndrome; MSA multiple system atrophy, DLB dementia with Lewy bodies; NCL neuronal ceroid-lipofuscinosis, HSP hereditary spastic paraplegia, INAD infantile neuroaxonal dystrophy, NAD neuroaxonal dystrophy, PTC premature termination codon, CNV copy number variation, LB+ positive for Lewy body pathology, LB- negative for Lewy body pathology; tau+, positive for tau pathology

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ISSN: 2051-5960

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