Buscar en
Neurología (English Edition)
Toda la web
Inicio Neurología (English Edition) Parkinson's disease secondary to 2 mutations of genes involved in lysosomal ...
Journal Information
Vol. 35. Issue 8.
Pages 611-612 (October 2020)
Vol. 35. Issue 8.
Pages 611-612 (October 2020)
Letter to the Editor
Open Access
Parkinson's disease secondary to 2 mutations of genes involved in lysosomal protein degradation
Enfermedad de Parkinson por sendas mutaciones en 2 genes relacionados con la degradación por lisosomas
G. Fernández-Pajarín
Corresponding author

Corresponding author.
, A. Sesar, B. Ares-Pensado, A. Castro
Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospital Clínico Universitario de Santiago, Santiago de Compostela, La Coruña, Spain
Article information
Full Text
Download PDF
Full Text
Dear Editor:

The precise mechanisms of neuronal degeneration in Parkinson's disease (PD) are yet to be determined. We already know of several cellular alterations that contribute to neuronal damage to differing degrees. These include alterations in protein processing, oxidative stress, mitochondrial dysfunction, inflammatory and excitotoxic mechanisms, or intracellular vesicular transport alterations. Impaired neuronal autophagy is currently considered one of the main mechanisms related to PD; specifically, primary lysosomal defects may promote the formation of Lewy bodies.1

We present the case of a 71-year-old man diagnosed with PD at the age of 68, who presented mild, predominantly right-sided parkinsonian syndrome and resting tremor in the right hand. He showed good response to treatment with low doses of levodopa (300mg/day) and dopaminergic agonists (extended-release pramipexole at 1.05mg/day). Cognitive performance was consistent with his age and level of education. Regarding non-motor symptoms, he reported frequent nightmares and sleep talking, associated with a probable REM sleep behaviour disorder; however, he did not present hyposmia or hypogeusia. His sister, living in Venezuela, was diagnosed with PD at the age of 75.

A genetic study of the patient revealed 2 mutations in genes associated with familial PD. The patient was a heterozygous carrier of a variant of the GBA gene, causing the amino acid isoleucine to be replaced by valine at codon 445 (1333A>G, Ile445Val). This is a novel mutation that may affect messenger RNA splicing mechanisms. The patient was also a heterozygous carrier of a variant of the ATP13A2 gene, causing the amino acid methionine to be replaced by lysine at codon 210 (629T>A, Met210Lys).

Neurons are extremely sensitive to alterations in protein degradation pathways. α-Synuclein is the main component of Lewy bodies. It is degraded by both the ubiquitin-proteasome system and the lysosomal system. While α-synuclein accumulation may partly be caused by dysfunction of proteolytic systems, it may also cause this dysfunction, as it is known to reduce the activity of these systems.2 Furthermore, mutations in PD-associated genes such as LRRK2, parkin, and PINK1 have been associated with decreased autophagic degradation.

Some genes coding for such lysosomal proteins as glucocerebrosidase (GBA) and ATP13A2 (encoding a lysosomal type 5 P-type ATPase), have been associated with familial PD.3GBA mutations in homozygosis or compound heterozygosis are responsible for Gaucher disease, the most frequent disorder of lysosomal storage. Heterozygous mutations cause partial loss of the enzyme's function, leading to a reduction in the lysosomal degradation of α-synuclein. These heterozygous mutations are currently the most significant known genetic risk factor in PD, multiplying the risk of developing PD by 20 with respect to non-carriers.4 Mutations in the ATP13A2 gene are responsible for severe parkinsonism with good response to levodopa (Kufor-Rakeb syndrome or PARK9). Heterozygous mutations of this gene have been associated with greater predisposition to PD due to the loss of enzyme function, which causes alterations to intracellular zinc homeostasis.5 The resulting lysosomal dysfunction leads to greater accumulation of α-synuclein.6 Furthermore, the function of cathepsin D, a protease active in the lysosomal degradation of α-synuclein, is also diminished in the context of ATP13A2 mutation.7 In both enzyme defects, PD phenotype is undistinguishable from that of sporadic PD.

Our patient presented 2 mutations in genes associated with lysosomal enzyme activity that cause an impairment of lysosome-mediated autophagy and accumulation of α-synuclein in neurons. This pathogenic mechanism is an area of increasing interest in PD, not only because of its pathogenic role but also because it may represent a line of research for neuroprotective treatment.1 We suggest that both mutations may even have a synergistic effect for the patient; the genetic study of the patient's sister would confirm the pathogenicity of both mutations; however, this was not possible.

B. Dehay, M. Martinez-Vicente, G.A. Caldwell, K.A. Caldwell, Z. Yue, M.R. Cookson, et al.
Lysosomal impairment in Parkinson's disease.
Mov Disord, 28 (2013), pp. 725-732
M. Martinez-Vicente, Z. Talloczy, S. Kaushik, A.C. Massey, J. Mazzulli, E.V. Mosharov, et al.
Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy.
J Clin Invest, 118 (2008), pp. 777-788
S. Sato, Y. Li, N. Hattori.
Lysosomal defects in ATP13A2 and GBA associated familial Parkinson's disease.
J Neural Transm (Vienna), 124 (2017), pp. 1395-1400
K.E. Murphy, A.M. Gysbers, S.K. Abbott, N. Tayebi, W.S. Kim, E. Sidransky, et al.
Reduced glucocerebrosidase is associated with increased a-synuclein in sporadic Parkinson's disease.
Brain, 137 (2014), pp. 834-848
J.S. Park, N.F. Blair, C.M. Sue.
The role of ATP13A2 in Parkinson's disease: clinical phenotypes and molecular mechanisms.
Mov Disord, 30 (2015), pp. 770-779
M. Usenovic, E. Tresse, J.R. Mazzulli, J.P. Taylor, D. Krainc.
Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity.
J Neurosci, 32 (2012), pp. 4240-4246
H. Matsui, F. Sato, S. Sato, M. Koike, Y. Taruno, S. Saiki, et al.
ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons.
FEBS Lett, 587 (2013), pp. 1316-1325

Please cite this article as: Fernández-Pajarín G, Sesar A, Ares-Pensado B, Castro A. Enfermedad de Parkinson por sendas mutaciones en 2 genes relacionados con la degradación por lisosomas. Neurología. 2020;35:611–612.

Copyright © 2019. Sociedad Española de Neurología
Article options
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos