The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases

Pradhan, Lilesh Kumar; Das, Saroj Kumar

doi:10.1007/s10571-020-00893-4

Cited by 8 publications

(5 citation statements)

References 184 publications

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“…It is intriguing to speculate that an increase in Nogo-A expression in DA neurons underlies compensatory adaptations to cope with mild or acute degenerative conditions, such as those occurring in aging in humans or those exerted by 6-OHDA in rats, respectively. There is growing evidence that Nogo participates in different processes related to apoptosis and autophagy [ 36 , 37 ]. However, whether Nogo-A plays a direct role in regulating the dopaminergic neurons viability in healthy and diseased brains is currently not known.…”

Section: Discussionmentioning

confidence: 99%

Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease

Eyer

Santo

Hewer

et al. 2021

Cells

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Parkinson’s disease is mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Together with the small number, the high vulnerability of the dopaminergic neurons is a major pathogenic culprit of Parkinson’s disease. Our previous findings of a higher survival of dopaminergic neurons in the substantia nigra co-expressing Nogo-A in an animal model of Parkinson’s disease suggested that Nogo-A may be associated with dopaminergic neurons resilience against Parkinson’s disease neurodegeneration. In the present study, we have addressed the expression of Nogo-A in the dopaminergic neurons in the substantia nigra in postmortem specimens of diseased and non-diseased subjects of different ages. For this purpose, in a collaborative effort we developed a tissue micro array (TMA) that allows for simultaneous staining of many samples in a single run. Interestingly, and in contrast to the observations gathered during normal aging and in the animal model of Parkinson’s disease, increasing age was significantly associated with a lower co-expression of Nogo-A in nigral dopaminergic neurons of patients with Parkinson’s disease. In sum, while Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in Parkinson’s disease. These observations suggest that Nogo-A might play a substantial role in the vulnerability of dopaminergic neurons in Parkinson’s disease.

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Section: Discussionmentioning

confidence: 99%

Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease

Eyer

Santo

Hewer

et al. 2021

Cells

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“…RTNs possess a conserved C-terminal RTN homology domain characterized by two unusually long hydrophobic regions interrupted by a hydrophilic loop (Chiurchiù et al, 2014). The hydrophobic parts of the RTN domain inserted into lipid bilayers have an unusual hairpin topology between the inner and outer shear controlling the shape of the ER membrane (Pradhan and Das, 2021). These proteins are abundant in the tubular ER and play a critical role in interorganelle communication between the ER and mitochondria (Hübner and Kurth, 2014;Voeltz et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins are abundant in the tubular ER and play a critical role in interorganelle communication between the ER and mitochondria (Hübner and Kurth, 2014;Voeltz et al, 2006). Some protein-encoding HSP genes, including ARL6IP1, REEP1, ALT1, and SPAST, have been identified as RTNs localized in the ER membrane (Hübner and Kurth, 2014;Voeltz et al, 2006); these play a critical role in shaping the ER, connecting intracellular membrane-bound organelles, and are intrinsic in neurodegenerative disease pathogenesis (Chiurchiù et al, 2014;Pradhan and Das, 2021). ARL6IP1 is an anti-apoptotic regulator of the ER membrane (Lui et al, 2003); its depletion induced neuronal cell death and reduced neuronal axonal outgrowth and extension by inhibiting autophagy signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

ARL6IP1 gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model

Lim,

Kang,

Kim

et al. 2023

Journal of Experimental Medicine

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ARL6IP1 is implicated in hereditary spastic paraplegia (HSP), but the specific pathogenic mechanism leading to neurodegeneration has not been elucidated. Here, we clarified the molecular mechanism of ARL6IP1 in HSP using in vitro and in vivo models. The Arl6ip1 knockout (KO) mouse model was generated to represent the clinically involved frameshift mutations and mimicked the HSP phenotypes. Notably, in vivo brain histopathological analysis revealed demyelination of the axon and neuroinflammation in the white matter, including the corticospinal tract. In in vitro experiments, ARL6IP1 silencing caused cell death during neuronal differentiation and mitochondrial dysfunction by dysregulated autophagy. ARL6IP1 localized on mitochondria-associated membranes (MAMs) to maintain endoplasmic reticulum and mitochondrial homeostasis via direct interaction with LC3B and BCl2L13. ARL6IP1 played a crucial role in connecting the endoplasmic reticulum and mitochondria as a member of MAMs. ARL6IP1 gene therapy reduced HSP phenotypes and restored pathophysiological changes in the Arl6ip1 KO model. Our results established that ARL6IP1 could be a potential target for HSP gene therapy.

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“…The main obstacles to understanding how RTNs might cause HSP disease are, first, the difficulty in sorting out the phenotypes associated with loss of RTNs function and, second, their putative general involvement in neurodegeneration. RTNs have indeed been implicated in several neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and multiple sclerosis [ 72 , 73 ], although a mechanistic understanding of a possible causal link between the neurodegenerative process and RTNs function is still lacking.…”

Section: Er Shaping Proteinsmentioning

confidence: 99%

“…However, their collective role also remains vague. First, because the loss of multiple RTNs in cells and yeast has consequences that are not always consistent with their putative function [ 69 , 79 ], and second because the differential expression of the four RTNs in different tissues and cell types (i.e., RTN1 and RTN3 expression is essentially limited to the nervous system [ 72 , 77 , 78 ] and RTN4 is expressed ubiquitously [ 66 , 80 ]) complicates our understanding of their various functional combinations. These experimental observations make it difficult to envisage why so many different RTN isoforms with overlapping functions should have evolved, cooperating in different combinations to eventually achieve the identical result of generating the membrane curvature typical of ER tubules and sheet edges.…”

Section: Er Shaping Proteinsmentioning

confidence: 99%

ER Morphology in the Pathogenesis of Hereditary Spastic Paraplegia

Sonda

Pendin

Daga

2021

Cells

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The endoplasmic reticulum (ER) is the most abundant and widespread organelle in cells. Its peculiar membrane architecture, formed by an intricate network of tubules and cisternae, is critical to its multifaceted function. Regulation of ER morphology is coordinated by a few ER-specific membrane proteins and is thought to be particularly important in neurons, where organized ER membranes are found even in the most distant neurite terminals. Mutation of ER-shaping proteins has been implicated in the neurodegenerative disease hereditary spastic paraplegia (HSP). In this review we discuss the involvement of these proteins in the pathogenesis of HSP, focusing on the experimental evidence linking their molecular function to disease onset. Although the precise biochemical activity of some ER-related HSP proteins has been elucidated, the pathological mechanism underlying ER-linked HSP is still undetermined and needs to be further investigated.

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The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases

Cited by 8 publications

References 184 publications

Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease

Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease

ARL6IP1 gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model

ER Morphology in the Pathogenesis of Hereditary Spastic Paraplegia

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