scholarly journals Extensive Leukoencephalopathy in Spastic Paraplegia Type 4: Possible Role of Cerebral Autosomal Arteriopathy With Subcortical Infarcts and Leukoencephelopathy

2021 ◽  
Author(s):  
Jin Ho Jung ◽  
Jung Hwa Seo ◽  
Sukyoon Lee ◽  
Young Jin Heo ◽  
Donghyun Kim ◽  
...  
Keyword(s):  
Spastic Paraplegia

scholarly journals Mouse models for hereditary spastic paraplegia uncover a role of PI4K2A in autophagic lysosome reformation

Autophagy ◽  
2021 ◽  
pp. 1-17
Author(s):  
Mukhran Khundadze ◽  
Federico Ribaudo ◽  
Adeela Hussain ◽  
Henry Stahlberg ◽  
Nahal Brocke-Ahmadinejad ◽  
...  
Keyword(s):  
Mouse Models ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

scholarly journals Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1678
Author(s):  
Liriopé Toupenet Marchesi ◽  
Marion Leblanc ◽  
Giovanni Stevanin
Keyword(s):  
Nervous System ◽  
Motor Neurons ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Current Knowledge ◽  
Spastic Paraplegia ◽  
Functional Convergence ◽  
The Common ◽  
Hsp Genes

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.

scholarly journals The role of spartin and its novel ubiquitin binding region in DALIS occurrence

2014 ◽  
Vol 25 (8) ◽  
pp. 1355-1365 ◽  
Author(s):  
Amelia B. Karlsson ◽  
Jacqueline Washington ◽  
Valentina Dimitrova ◽  
Christopher Hooper ◽  
Alexander Shekhtman ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Resonance Spectroscopy ◽  
Spastic Paraplegia ◽  
Binding Region ◽  
Hairpin Rna ◽  
Multifunctional Protein ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Key Residues

Troyer syndrome is an autosomal recessive hereditary spastic paraplegia (HSP) caused by frameshift mutations in the SPG20 gene that results in a lack of expression of the truncated protein. Spartin is a multifunctional protein, yet only two conserved domains—a microtubule-interacting and trafficking domain and a plant-related senescence domain involved in cytokinesis and mitochondrial physiology, respectively—have been defined. We have shown that overexpressed spartin binds to the Ile44 hydrophobic pocket of ubiquitin, suggesting spartin might contain a ubiquitin-binding domain. In the present study, we demonstrate that spartin contributes to the formation of dendritic aggresome-like induced structures (DALIS) through a unique ubiquitin-binding region (UBR). Using short hairpin RNA, we knocked down spartin in RAW264.7 cells and found that DALIS frequency decreased; conversely, overexpression of spartin increased the percentage of cells containing DALIS. Using nuclear magnetic resonance spectroscopy, we characterized spartin's UBR and defined the UBR's amino acids that are key for ubiquitin binding. We also found that spartin, via the UBR, binds Lys-63–linked ubiquitin chains but does not bind Lys-48–linked ubiquitin chains. Finally, we demonstrate that spartin's role in DALIS formation depends on key residues within its UBR.

scholarly journals A Novel SPAST/SPG4 Splice-Site Variant in a Family with Dominant Hereditary Spastic Paraplegia

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Nathaniel M. Robbins ◽  
Jillian R. Ozmore ◽  
Thomas L. Winder ◽  
Pedro Gonzalez-Alegre ◽  
Tanya M. Bardakjian
Keyword(s):  
Splice Site ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraparesis ◽  
Spastic Paraplegia ◽  
Novel Variant ◽  
Consensus Splice Site ◽  
Diagnostic Work ◽  
Next Generation Sequencing Ngs ◽  
Work Up

Some causes of spastic paraplegia are treatable and many are not. Diagnostic work-up to determine the etiology can be costly and invasive. Here we report the case of a man with slowly progressive spastic paraparesis. Using a multigene next-generation sequencing (NGS) panel, we identified a novel variant in the consensus splice site of the SPAST gene (exon 13, c.1536G>A, heterozygous), affecting codon 512 of the SPAST mRNA. The observed variant segregated with the disease in four tested family members. In this case, genetic confirmation obviated the need for additional testing such as MRI and lumbar puncture and helped the patient and his family understand his condition and prognosis. We conclude with a brief discussion of the SPG4/SPAST gene and the role of multigene panels in the diagnosis and management of hereditary spastic paraplegia.

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4–Associated Hereditary Spastic Paraplegia

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012836
Author(s):  
Darius Ebrahimi-Fakhari ◽  
Julian E Alecu ◽  
Marvin Ziegler ◽  
Gregory Geisel ◽  
Catherine Jordan ◽  
...  
Keyword(s):  
White Matter ◽  
Corpus Callosum ◽  
Brain Development ◽  
Hereditary Spastic Paraplegia ◽  
Anterior Commissure ◽  
Brain Mri ◽  
Adaptor Protein ◽  
Spastic Paraplegia ◽  
Mri Findings

Background and Objectives:AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radio-clinical correlations.Methods:A systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically-confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity.Results:We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor (“ears of the grizzly sign”), and (4) periventricular white matter abnormalities. The presence of two or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP, while the combination of all four is found in ∼45% of cases. Compared to other HSP with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis further identified a subset of AP-4-HSP patients with polymicrogyria, underscoring the role of AP-4 in early brain development. Of clinical importance, these patients displayed a higher prevalence of seizures and status epilepticus, many at a young age.Discussion:Our findings define the MRI spectrum of AP-4-HSP providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.

The role of hereditary spastic paraplegia related genes in multiple sclerosis

2007 ◽  
Vol 254 (9) ◽  
pp. 1221-1226 ◽  
Author(s):  
G. C. DeLuca ◽  
S. V. Ramagopalan ◽  
M. Z. Cader ◽  
D. A. Dyment ◽  
B. M. Herrera ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

scholarly journals The Role of ZFYVE27/Protrudin in Hereditary Spastic Paraplegia

2008 ◽  
Vol 83 (1) ◽  
pp. 127-128 ◽  
Author(s):  
Monica Martignoni ◽  
Elena Riano ◽  
Elena I. Rugarli
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia

scholarly journals Microtubule-dependent and independent roles of spastin in lipid droplet dispersion and biogenesis

2020 ◽  
Vol 3 (6) ◽  
pp. e202000715
Author(s):  
Nimesha Tadepalle ◽  
Lennart Robers ◽  
Matteo Veronese ◽  
Peter Zentis ◽  
Felix Babatz ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Mammalian Cells ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Plastic Behavior ◽  
Glucose Starvation ◽  
Spastic Paraplegia ◽  
Microtubule Severing ◽  
Tag Accumulation

Lipid droplets (LDs) are metabolic organelles that store neutral lipids and dynamically respond to changes in energy availability by accumulating or mobilizing triacylglycerols (TAGs). How the plastic behavior of LDs is regulated is poorly understood. Hereditary spastic paraplegia is a central motor axonopathy predominantly caused by mutations in SPAST, encoding the microtubule-severing protein spastin. The spastin-M1 isoform localizes to nascent LDs in mammalian cells; however, the mechanistic significance of this targeting is not fully explained. Here, we show that tightly controlled levels of spastin-M1 are required to inhibit LD biogenesis and TAG accumulation. Spastin-M1 maintains the morphogenesis of the ER when TAG synthesis is prevented, independent from microtubule binding. Moreover, spastin plays a microtubule-dependent role in mediating the dispersion of LDs from the ER upon glucose starvation. Our results reveal a dual role of spastin to shape ER tubules and to regulate LD movement along microtubules, opening new perspectives for the pathogenesis of hereditary spastic paraplegia.

A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration

2020 ◽  
Vol 31 (4) ◽  
pp. 351-362 ◽  
Author(s):  
Alessio Guglielmi
Keyword(s):  
Neurodegenerative Diseases ◽  
Sigmund Freud ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Dna Analysis ◽  
Therapeutic Strategies ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Adolf Von Strümpell

AbstractAt the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3–9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.

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