Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts

Kilpatrick, Bethan S.; Magalhaes, Joana; Beavan, Michelle; McNeill, Alisdair; Gegg, Matthew E.; Cleeter, M. W. J.; Bloor-Young, Duncan; Churchill, Grant C.; Duchen, Michael R.; Schapira, Anthony H.V.; Patel, Sandip

doi:10.1016/j.ceca.2015.11.002

Cited by 69 publications

(63 citation statements)

References 41 publications

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“…; Kilpatrick et al . ). Furthermore, dopaminergic neurons derived from pluripotent stem cells of GBA‐associated PD patients not only display lysosomal and autophagic dysfunction but also elevated intracellular Ca 2+ levels and impaired calcium homeostasis (Schondorf et al .…”

Section: Impaired Calcium Homeostasis Mitochondrial and Lysosomal Dymentioning

confidence: 97%

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Duda¹,

Pötschke²,

Liss³

2016

Journal of Neurochemistry

136

131

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Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium-and activity-dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2-autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double-edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed-forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD-paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD-triggers, as well as on bidirectional functions of voltage-gated L-type calcium channels and

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Section: Impaired Calcium Homeostasis Mitochondrial and Lysosomal Dymentioning

confidence: 97%

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Duda¹,

Pötschke²,

Liss³

2016

Journal of Neurochemistry

136

131

View full text Add to dashboard Cite

show abstract

“…Finally, Schöndorf and colleagues observed an increased level of cytosolic Ca2+ in neurons derived from iPSC of GBA mutation carriers (Schöndorf et al 2014). Accumulation of misfolded mutant GCase into the ER leads to dysfunction of the UPR (Kurzawa-Akanbi et al 2012; Fernandes et al 2016) and can perturb ER related Ca2+ homeostasis (Kilpatrick et al 2016). The fact that GBA mutations appear as a risk factor for PD in the heterozygous state shows that one healthy allele may be enough to ensure normal cellular function for a certain time; however, during ageing, mutant cells cannot cope anymore with lysosomal and mitochondrial dysfunctions associated to alpha-synuclein accumulation.…”

Section: Genetic Risk Factors Linked To Impaired Mitochondrial Functimentioning

confidence: 99%

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

2018

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Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17–23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

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“…Lysosome dysfunction is implicated along multiple lines of evidence in neurodegenerative disease - AD, Parkinson’s Disease and Huntington’s Disease in particular [13,32,48,65,72,93,119]. Among the numerous molecular pathway links to AD, PS knockout and expression of FAD PS1 have been found to increase Ca 2+ release from lysosomes [31,79].…”

Section: Emerging Ca2+ Sourcesmentioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts

Abstract: Graphical abstract

Cited by 69 publications

References 41 publications

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

Emerging pathways driving early synaptic pathology in Alzheimer's disease

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