Progressive decline of glucocerebrosidase in aging and
            <scp>P</scp>
            arkinson's disease

Rocha, Emily M.; Smith, Gaynor A.; Park, Eric; Cao, Hongmei; Brown, Eilish; Hallett, Peter; Isacson, Ole

doi:10.1002/acn3.177

Cited by 168 publications

(169 citation statements)

References 18 publications

(27 reference statements)

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…As a consequence of this genetic link, attention is being focused on uncovering the relationship between GCase and sporadic PD, which should give insight into the pathophysiology of the disease. Several studies, including our own, have demonstrated a reduction of GCase activity in the brain of sporadic PD patients (Gegg et al, 2012;Rocha et al, 2015a), and our data also showed that reduced GCase activity is paralleled by increased levels of the glycolipid substrate glucosylsphingosine. Moreover, we have shown that there is a progressive age-dependent reduction in GCase activity in healthy subjects in brain regions most affected in PD (Rocha et al, 2015a).…”

Section: Introductionsupporting

confidence: 76%

“…Lysosomal degradation systems, as well as GCase are known to gradually decline with aging (Martinez-Vicente et al, 2005;Rocha et al, 2015a). Moreover, there is an age-dependent reduction in GCase activity in healthy subjects in the brain regions most affected in PD (Rocha et al, 2015a).…”

Section: Overexpression Of Gcase Protected Dopaminergic Neurons In Thmentioning

confidence: 99%

“…GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase) and clinical and neuropathological evidence links GBA1 to PD and related -synucleinopathies (Eblan et al, 2006;Gegg et al, 2012;Neumann et al, 2009;Rocha et al, 2015a;Sidransky et al, 2009;Velayati et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons

Rocha

Smith

Park

et al. 2015

Neurobiology of Disease

Self Cite

124

View full text Add to dashboard Cite

Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including α-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related α-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of α-synuclein and protect midbrain dopamine neurons from α-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype α-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant α-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of α-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T α-synuclein into the substantia nigra prevented α-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of α-synuclein.

show abstract

Section: Introductionsupporting

confidence: 76%

Section: Overexpression Of Gcase Protected Dopaminergic Neurons In Thmentioning

confidence: 99%

See 1 more Smart Citation

Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons

Rocha

Smith

Park

et al. 2015

Neurobiology of Disease

Self Cite

124

View full text Add to dashboard Cite

show abstract

“…S13). Recent studies have shown that elevations in GCase substrates can be documented when measured from certain circumscribed brain regions of PD patients (with or without GBA1 mutations) (33). However, other studies of GBA1 heterozygous mice have shown no changes in Shown is MW in kDa.…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein–induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

Mazzulli

Zunke

Isacson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

295

309

View full text Add to dashboard Cite

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

show abstract

“…Neurodegenerative diseases typically occur in older individuals, so perhaps even subtle, barely measurable changes in lysosome biology will predispose an individual to a neurodegenerative disease. This concept is supported by observations that several cellular organelles, including the lysosome, become less effective with age 11 . It might take only small changes in the accumulation of substances in the lysosome to induce neurodegenerative diseases later in life.…”

Section: Balancing Actmentioning

confidence: 73%