Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Tayebi, Nahid; Parisiadou, Loukia; Berhe, Bahafta; Gonzalez, Ashley N.; Serra-Vinardell, Jenny; Tamargo, Raphael J.; Maniwang, Emerson; Sorrentino, Zachary A.; Fujiwara, Hideji; Grey, Richard; Hassan, Shahzeb; Blech-Hermoni, Yotam; Chen, Chuyu; McGlinchey, Ryan P.; Makariou-Pikis, Chrissy; Brooks, Michael C.; Ginns, Edward I.; Ory, Daniel S.; Giasson, Benoit I.; Sidransky, Ellen

doi:10.1016/j.ymgme.2017.11.001

Cited by 32 publications

(37 citation statements)

References 45 publications

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“…Accumulation of GlcCer and lower levels of LacCer in the DRGs suggest that the lysosomal metabolism of GlcCer via glucocerebrosides (GBA1) to LacCer is impaired, which would agree with associations of GBA1 dysfunctions with PD [28], and with increased alpha synuclein toxicity in the presence of GBA1 mutations [27,29,47]. Gene expression analysis (RNAseq) in the DRGs of our mice did not reveal lower GBA1 transcription (Suppl.…”

Section: Accumulation Of Glucosylceramides In Drgs and Loss Of Sphingsupporting

confidence: 77%

“…In addition, it has been recognized in recent years that metabolic deregulations of bioactive lipids including ceramides and their metabolites increase the toxicity of alpha-synuclein [25][26][27]. Patients who are heterozygous carriers of glucocerebrosidase (GBA1) mutations tend to develop a rapidly progressive disease [28], and such mutations propagate alpha synuclein deposition in PD model organisms [29][30][31][32]. GBA1 is a lysosomal enzyme that catalyzes the degradation of ceramides to glucosylceramides (GlcCer) and subsequent generation of lactosylceramides (LacCer) and gangliosides.…”

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confidence: 99%

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Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Valek¹,

Tran²,

Wilken-Schmitz³

et al. 2020

Preprint

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BACKGROUND: Parkinson's Disease (PD) is frequently associated with a prodromal sensory neuropathy, which manifests as sensory loss and eventually chronic pain. METHODS: The present study assessed somatosensory functions and the pathology of somatosensory neurons in Pink1-/-SNCAA53T double mutant mice (Pink1SNCA) who develop a PD-like disease > 15 months of age. RESULTS: Pink1SNCA mice showed the first manifestations of sensory dysfunctions at 6 months of age, which were characterized by a loss of thermal sensitivity but sparing of mechanical sensation, and decline of olfactory perception of pleasant odors. Mechanistically, the loss of thermal sensitivity was attributed to a strong reduction of transient receptor potential TRPV and TRPA channels at mRNA, protein and functional levels in the dorsal root ganglia (DRGs). Primary sensory neurons responded much less to stimulations with capsaicin, formalin or depolarization as assessed by calcium imaging. RNA sequencing pointed to additional deregulations of voltage dependent potassium channel subtypes, lowering of acidic fibroblast growth factor driven support, and alterations of sphingolipid metabolism. Analyses of sphingolipids of multiple classes revealed an accumulation of glucosylceramides mainly in the DRGs and loss of sphingosines and sphinganines in the sciatic nerve. Transmission electron microscopy of the DRGs revealed a higher frequency of neurons with swollen mitochondria, which was associated with a decrease of mitochondrial respiration in sensory ganglia, but not in the brain. CONCLUSION: The data support the view of a prodromal sensory disease in PD resulting from a combination of lipid allostasis and mitochondrial damage. Hence, Pink1SNCA mice phenocopy the PD-associated prodromal sensory neuropathy and reveal novel mechanistic insight.

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Section: Accumulation Of Glucosylceramides In Drgs and Loss Of Sphingsupporting

confidence: 77%

mentioning

confidence: 99%

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Valek¹,

Tran²,

Wilken-Schmitz³

et al. 2020

Preprint

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“…The hypothesis that GBA1 could affect α-synuclein degradation and pathology has been tested in several animal models [ 8 , 10 , 30 , 37 , 44 ]. These models have allowed us to elucidate the relationship among GBA1, α-synuclein, and PD.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the early-onset PD was identified in the patients with low GBA1 enzyme activity through an imaging study [ 21 ]. Several studies attempted to define the effect of GBA1 deficiency on α-synuclein accumulation, turn over and its consequent pathology in vivo [ 8 , 10 , 30 , 37 , 44 ]. Although the studies have partially relationship among GBA1, α-synuclein, and PD, the animal models fail to represent GBA1-associated Parkinsonism, lacking an earlier age of PD onset and dopaminergic neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model

Kim

Hwang

Choi

et al. 2018

acta neuropathol commun

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Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson’s disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T α-synuclein induced α-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T α-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of α-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T α-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T α-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related α-synucleinopathies.

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“…While it is generally believed that in autosomal recessive diseases the heterozygotes are phenotypically normal, it is increasingly evident that haploinsufficiency of a gene product may lead to phenotypic manifestations that are different from that of the complete absence of the same gene product. For example, while the complete deficiency of β‐GBA causes type‐2 Gaucher's disease, haploinsufficiency of β‐GBA may manifest as Parkinson's disease in humans and in mice . Moreover, it has been reported that while complete ablation of the CLN11 gene encoding progranulin causes NCL11‐disease in humans and in mice, its haploinsufficiency manifests as frontotemporal dementia .…”

Section: Discussionmentioning

confidence: 99%

Cln3‐mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl‐protein thioesterases‐1 (Ppt1)‐protein and Ppt1‐enzyme activity in the lysosome

Appu

Bagh

Sadhukhan

et al. 2019

J of Inher Metab Disea

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Mutations in at least 13 different genes (called CLNs) underlie various forms of neuronal ceroid lipofuscinoses (NCLs), a group of the most common neurodegenerative lysosomal storage diseases. While inactivating mutations in the CLN1 gene, encoding palmitoyl‐protein thioesterases‐1 (PPT1), cause infantile NCL (INCL), those in the CLN3 gene, encoding a protein of unknown function, underlie juvenile NCL (JNCL). PPT1 depalmitoylates S‐palmitoylated proteins (constituents of ceroid) required for their degradation by lysosomal hydrolases and PPT1‐deficiency causes lysosomal accumulation of autofluorescent ceroid leading to INCL. Because intracellular accumulation of ceroid is a characteristic of all NCLs, a common pathogenic link for these diseases has been suggested. It has been reported that CLN3‐mutations suppress the exit of cation‐independent mannose 6‐phosphate receptor (CI‐M6PR) from the trans Golgi network (TGN). Because CI‐M6PR transports soluble proteins such as PPT1 from the TGN to the lysosome, we hypothesized that CLN3‐mutations may cause lysosomal PPT1‐insufficiency contributing to JNCL pathogenesis. Here, we report that the lysosomes in Cln3‐mutant mice, which mimic JNCL, and those in cultured cells from JNCL patients, contain significantly reduced levels of Ppt1‐protein and Ppt1‐enzyme activity and progressively accumulate autofluorescent ceroid. Furthermore, in JNCL fibroblasts the V0a1 subunit of v‐ATPase, which regulates lysosomal acidification, is mislocalized to the plasma membrane instead of its normal location on lysosomal membrane. This defect dysregulates lysosomal acidification, as we previously reported in Cln1 −/− mice, which mimic INCL. Our findings uncover a previously unrecognized role of CLN3 in lysosomal homeostasis and suggest that CLN3‐mutations causing lysosomal Ppt1‐insuffiiciency may at least in part contribute to JNCL pathogenesis.

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Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Cited by 32 publications

References 45 publications

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model

Cln3‐mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl‐protein thioesterases‐1 (Ppt1)‐protein and Ppt1‐enzyme activity in the lysosome

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