Parkinsonisms and Glucocerebrosidase Deficiency: A Comprehensive Review for Molecular and Cellular Mechanism of Glucocerebrosidase Deficiency

• Main Authors: Emilia M. Gatto, Gustavo Da Prat, Jose Luis Etcheverry, Guillermo Drelichman, Martin Cesarini
• Format: Article
• Language: English
• Published: MDPI AG 2019-02-01
• Series: Brain Sciences
• Subjects: glucocerebrosidase; Parkinson’s disease; Gaucher disease
• Online Access: https://www.mdpi.com/2076-3425/9/2/30

In the last years, lysosomal storage diseases appear as a bridge of knowledge between rare genetic inborn metabolic disorders and neurodegenerative diseases such as Parkinson&#8217;s disease (PD) or frontotemporal dementia. Epidemiological studies helped promote research in the field that continues to improve our understanding of the link between mutations in the glucocerebrosidase (<i>GBA</i>) gene and PD. We conducted a review of this link, highlighting the association in <i>GBA</i> mutation carriers and in Gaucher disease type 1 patients (GD type 1). A comprehensive review of the literature from January 2008 to December 2018 was undertaken. Relevance findings include: (1) There is a bidirectional interaction between GBA and &#945;- synuclein in protein homeostasis regulatory pathways involving the clearance of aggregated proteins. (2) The link between GBA deficiency and PD appears not to be restricted to &#945;&#8315;synuclein aggregates but also involves <i>Parkin</i> and <i>PINK1</i> mutations. (3) Other factors help explain this association, including early and later endosomes and the lysosomal-associated membrane protein 2A (LAMP-2A) involved in the chaperone-mediated autophagy (CMA). (4) The best knowledge allows researchers to explore new therapeutic pathways alongside substrate reduction or enzyme replacement therapies.