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Nature Cell Biology Aug 2023Lipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular...
Lipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular mechanisms mediating LD degradation by selective autophagy (lipophagy) are unknown. Here we identify spartin as a receptor localizing to LDs and interacting with core autophagy machinery, and we show that spartin is required to deliver LDs to lysosomes for triglyceride mobilization. Mutations in SPART (encoding spartin) lead to Troyer syndrome, a form of complex hereditary spastic paraplegia. Interfering with spartin function in cultured human neurons or murine brain neurons leads to LD and triglyceride accumulation. Our identification of spartin as a lipophagy receptor, thus, suggests that impaired LD turnover contributes to Troyer syndrome development.
Topics: Mice; Humans; Animals; Spastic Paraplegia, Hereditary; Lipid Droplets; Cell Cycle Proteins; Carrier Proteins; Autophagy; Triglycerides; Lipid Metabolism
PubMed: 37443287
DOI: 10.1038/s41556-023-01178-w -
Continuum (Minneapolis, Minn.) Feb 2024This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron... (Review)
Review
OBJECTIVE
This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy.
LATEST DEVELOPMENTS
Advances in genetic testing have vastly enhanced current knowledge of genetic myelopathies and the ability to diagnose and provide appropriate counseling to patients and their families. However, potential health care disparities in access to genetic testing is a topic that must be further explored. Although treatment for most of these conditions is typically supportive, there have been recent therapeutic breakthroughs in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy, and Friedreich ataxia.
ESSENTIAL POINTS
Genetic myelopathies may present with chronic and progressive symptoms, a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Imaging often shows spinal cord atrophy, but cord signal change is rare. Exclusion of reversible causes of myelopathy is a key step in the diagnosis. There are many different causes of genetic myelopathies, and in some cases, symptoms may overlap, which underscores the utility of genetic testing in confirming the precise underlying neurologic condition.
Topics: Humans; Amyotrophic Lateral Sclerosis; Muscular Atrophy, Spinal; Spastic Paraplegia, Hereditary; Spinal Cord Diseases
PubMed: 38330475
DOI: 10.1212/CON.0000000000001377 -
Frontiers in Neurology 2023ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early... (Review)
Review
ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.
PubMed: 38249738
DOI: 10.3389/fneur.2023.1252400 -
Arquivos de Neuro-psiquiatria Nov 2023Hereditary or familial spastic paraplegias (SPG) comprise a group of genetically and phenotypically heterogeneous diseases characterized by progressive degeneration... (Review)
Review
BACKGROUND
Hereditary or familial spastic paraplegias (SPG) comprise a group of genetically and phenotypically heterogeneous diseases characterized by progressive degeneration of the corticospinal tracts. The complicated forms evolve with other various neurological signs and symptoms, including movement disorders and ataxia.
OBJECTIVE
To summarize the clinical descriptions of SPG that manifest with movement disorders or ataxias to assist the clinician in the task of diagnosing these diseases.
METHODS
We conducted a narrative review of the literature, including case reports, case series, review articles and observational studies published in English until December 2022.
RESULTS
Juvenile or early-onset parkinsonism with variable levodopa-responsiveness have been reported, mainly in SPG7 and SPG11. Dystonia can be observed in patients with SPG7, SPG11, SPG22, SPG26, SPG35, SPG48, SPG49, SPG58, SPG64 and SPG76. Tremor is not a frequent finding in patients with SPG, but it is described in different types of SPG, including SPG7, SPG9, SPG11, SPG15, and SPG76. Myoclonus is rarely described in SPG, affecting patients with SPG4, SPG7, SPG35, SPG48, and SPOAN (spastic paraplegia, optic atrophy, and neuropathy). SPG4, SPG6, SPG10, SPG27, SPG30 and SPG31 may rarely present with ataxia with cerebellar atrophy. And autosomal recessive SPG such as SPG7 and SPG11 can also present with ataxia.
CONCLUSION
Patients with SPG may present with different forms of movement disorders such as parkinsonism, dystonia, tremor, myoclonus and ataxia. The specific movement disorder in the clinical manifestation of a patient with SPG may be a clinical clue for the diagnosis.
Topics: Humans; Spastic Paraplegia, Hereditary; Mutation; Tremor; Dystonia; Movement Disorders; Ataxia; Parkinsonian Disorders; Proteins
PubMed: 38035585
DOI: 10.1055/s-0043-1777005 -
Ageing Research Reviews Aug 2023PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features.... (Review)
Review
PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.
Topics: Humans; Neurodegenerative Diseases; Parkinsonian Disorders; Neuroaxonal Dystrophies; Genetic Association Studies; Mutation; Group VI Phospholipases A2
PubMed: 37236368
DOI: 10.1016/j.arr.2023.101957 -
Headache Jun 2024A cerebrospinal fluid (CSF) leak developed in a 14-year-old girl and a 12-year-old boy following a diagnostic lumbar puncture. Two days and sixteen years later,...
A cerebrospinal fluid (CSF) leak developed in a 14-year-old girl and a 12-year-old boy following a diagnostic lumbar puncture. Two days and sixteen years later, respectively, paraplegia developed due to a functional disorder. Imaging revealed an extensive extradural CSF collection in both patients and digital subtraction myelography was required to pinpoint the exact site of a ventral dural puncture hole where the lumbar spinal needle had gone "through and through" the dural sac. The CSF leak was complicated by cortical vein thrombosis in one patient. Both patients underwent uneventful surgical repair of the ventral dural puncture hole with prompt resolution of the paraplegia. Iatrogenic ventral CSF leaks may become exceptionally long standing and may be complicated by paraplegia on a functional basis both in the acute and chronic phases.
PubMed: 38860510
DOI: 10.1111/head.14749 -
Annals of Cardiothoracic Surgery Sep 2023Surgical and interventional repair of thoracoabdominal aortic aneurysms improve survival significantly compared to the natural history of the disease. However, both... (Review)
Review
Surgical and interventional repair of thoracoabdominal aortic aneurysms improve survival significantly compared to the natural history of the disease. However, both strategies are associated with a substantial risk of spinal cord ischemia, which has been reported to occur-even in contemporary series by expert centers-in up to 12% of patients, depending on the extent of the disease. Following improved neurological outcomes after staged approaches in extensive clinical and long-term large animal studies, and the description of the "collateral network", the concept of "Minimally Invasive Staged Segmental Artery Coil Embolization" (MISACE) was introduced by Etz This concept of priming the collateral network in order to improve spinal cord blood supply showed promising experimental and early clinical outcomes, and consequently led to the initiation of the randomized controlled multicenter PAPAartis trial (Paraplegia Prevention in Aortic Aneurysm Repair by Thoracoabdominal Staging). This describes the background and rationale for this trial and gives an update on the current status.
PubMed: 37817856
DOI: 10.21037/acs-2023-scp-0062