Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis

Vercellino, Marco; Fenoglio, Chiara; Galimberti, Daniela; Mattioda, Alessandra; Chiavazza, Carlotta; Binello, E; Pinessi, Lorenzo; Giobbe, Dario; Scarpini, Elio; Cavalla, Paola

doi:10.1177/1352458515610646

Cited by 12 publications

(9 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several SNPs have been found to influence PGRN levels: rs5848 in GRN , rs646776 near SORT1, and rs1990622 near TMEM106B . The correlation between lower PGRN levels and the minor allele of rs5848 in our series is in line with findings from previous studies [ 10 , 12 , 25 ]. Probably microRNA-659 binds more efficiently to this minor allele, resulting in translational suppression of PGRN [ 26 ].…”

Section: Discussionsupporting

confidence: 93%

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Meeter

Patzke²,

Loewen³

et al. 2016

Dement Geriatr Cogn Disord Extra

View full text Add to dashboard Cite

Background: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02), plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials.

show abstract

Section: Discussionsupporting

confidence: 93%

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Meeter

Patzke²,

Loewen³

et al. 2016

Dement Geriatr Cogn Disord Extra

View full text Add to dashboard Cite

show abstract

“…In a study of over 7000 individuals with MS, a genetic burden score was not associated with disability . Other smaller studies have reported associations of several genetic variants and progression of disability but have not yet been replicated …”

Section: Cause Versus Course – Are the Risk Factors Different?mentioning

confidence: 99%

Environmental and genetic risk factors for MS: an integrated review

Waubant

Lucas

Mowry

et al. 2019

Ann Clin Transl Neurol

232

184

View full text Add to dashboard Cite

Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.

show abstract

“…On the other hand, Freria et al [271], upon analyzing spinal cord synapses, found that increased MHC-I expression in both astrocytes and microglia correlates with decreased immunostaining for synaptophysin, suggesting that MHC-I levels are inversely related to synaptic density. Genetic studies indicated that a cohort of MS patients possesses higher frequency of two progranulin alleles (rs9897526 A and rs5848 T) that are associated with increased disease severity and decreased progranulin expression levels [272]. In marked contrast, Vercellino et al [273] have provided evidence for strong expression of progranulin in activated microglia, macrophages and neurons around cortical lesions in MS patients.…”

Section: Synaptic Elimination Might Be Central For the Cognitive Declmentioning

confidence: 99%

Synaptic Elimination in Neurological Disorders

Cardozo

Lima

Maciel

et al. 2019

View full text Add to dashboard Cite

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.

show abstract

Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis

Abstract: GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.

Cited by 12 publications

References 17 publications

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Environmental and genetic risk factors for MS: an integrated review

Synaptic Elimination in Neurological Disorders

Contact Info

Product

Resources

About