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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 -
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 -
Journal of Neurology Aug 2023Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of...
BACKGROUND AND OBJECTIVES
Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.
METHODS
We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.
RESULTS
WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11).
DISCUSSION
In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.
Topics: Humans; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Frontotemporal Dementia; Motor Neuron Disease; Motor Neurons; Spastin; Proteins; Flavoproteins; Phosphoric Monoester Hydrolases
PubMed: 37133535
DOI: 10.1007/s00415-023-11746-7 -
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 -
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 -
Journal of Children's Orthopaedics Dec 2023The growing spine differs from the adult spine in several ways. Although tumors and infections cause only a small percentage of pediatric back pain incidences, delayed... (Review)
Review
The growing spine differs from the adult spine in several ways. Although tumors and infections cause only a small percentage of pediatric back pain incidences, delayed proper diagnosis and treatment may be disastrous. Benign lesions, such as osteoid osteoma, osteoblastoma, and aneurysmal bone cyst in the spine, are predominant during the first two decades of life, whereas malignant bony spinal tumors are rare. In the pediatric population, malignant spine tumors include osteosarcoma, Ewing's sarcoma, lymphoma, and metastatic neuroblastoma. Infections of the growing spine are rare, with the incidence of discitis peaking in patients under the age of 5 years and that of vertebral osteomyelitis peaking in older children. Spondylodiscitis is often a benign, self-limiting condition with low potential for bone destruction. Conservative treatments, including bedrest, immobilization, and antibiotics, are usually sufficient. Spinal tuberculosis is a frequently observed form of skeletal tuberculosis, especially in developing countries. Indications for surgical treatment include neurologic deficit, spinal instability, progressive kyphosis, late-onset paraplegia, and advanced disease unresponsive to nonoperative treatment. Spinal tumors and infections should be considered potential diagnoses in cases with spinal pain unrelated to the child's activity, accompanied by fever, malaise, and weight loss. In spinal tumors, early diagnosis, fast and adequate multidisciplinary management, appropriate en bloc resection, and reconstruction improve local control, survival, and quality of life. Pyogenic, hematogenous spondylodiscitis is the most common spinal infection; however, tuberculosis-induced spondylodiscitis should also be considered. level 4.
PubMed: 38050596
DOI: 10.1177/18632521231215857 -
The Journal of Clinical Investigation Jul 2023The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset...
The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.
Topics: Humans; Spastic Paraplegia, Hereditary; Lipid Metabolism; Mutation; Golgi Apparatus; Lipids; Phenotype; Cell Cycle Proteins
PubMed: 37463447
DOI: 10.1172/JCI162836