Abstract:
:Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.
journal_name
Acta Neuropatholjournal_title
Acta neuropathologicaauthors
Rocchi A,Milioto C,Parodi S,Armirotti A,Borgia D,Pellegrini M,Urciuolo A,Molon S,Morbidoni V,Marabita M,Romanello V,Gatto P,Blaauw B,Bonaldo P,Sambataro F,Robins DM,Lieberman AP,Sorarù G,Vergani L,Sandri M,Pennutodoi
10.1007/s00401-016-1550-4subject
Has Abstractpub_date
2016-07-01 00:00:00pages
127-44issue
1eissn
0001-6322issn
1432-0533pii
10.1007/s00401-016-1550-4journal_volume
132pub_type
杂志文章abstract::A monoclonal antibody, raised against extracts from Alzheimer brain, that recognizes a phosphorylated epitope in high molecular weight neurofilament proteins and tau proteins also immunostains Alzheimer neurofibrillary tangles, neurites in senile plaques and granulovacuolar degeneration. This result suggest that granu...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686619
更新日期:1987-01-01 00:00:00
abstract::Among the various mechanisms proposed to explain the pathogenesis of cerebral lesions in human immunodeficiency virus (HIV)-induced encephalitis, a cytokine-mediated action has found most favour. Indeed, elevated expression of cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha), thought to...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050457
更新日期:1996-01-01 00:00:00
abstract::To assess whether amyloid plaque accumulation in the monkey brain can account for age-related cognitive impairment that begins at about 20 years of age, we measured plaque content in the brains of 14 rhesus monkeys aged 5-30 years. We used immunohistochemistry employing the monoclonal antibody 6E10, which is specific ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050735
更新日期:1997-11-01 00:00:00
abstract::A massive expansion of a GGGGCC repeat upstream of the C9orf72 coding region is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization and lack of a canonical start codon, both strands are translated into aggregating dipeptide repeat (DPR) proteins: ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-015-1450-z
更新日期:2015-10-01 00:00:00
abstract::Rat sciatic nerve was assayed for total collagen and total protein both immediately post-mortem and at weekly intervals after death. No significant difference was found in collagen and protein content between corresponding nerve segments assayed fresh and up to 4 weeks post mortem. However, variation was found in peri...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00692870
更新日期:1980-01-01 00:00:00
abstract::We performed a comparative study to assess cerebral amyloid angiopathy and ApoE genotype in cases of Alzheimer's disease (AD). Ten ApoE 3,3 and ten ApoE 4,4 AD brains, as well as ten normal control brains, were selected after matching for age, sex, and duration of disease. Sections of middle frontal and inferior parie...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-006-0162-9
更新日期:2007-01-01 00:00:00
abstract::Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-010-0770-2
更新日期:2011-02-01 00:00:00
abstract::Frontotemporal lobar degeneration is the term used to describe the non-Alzheimer clinical syndromes of frontotemporal dementia, semantic dementia and progressive non-fluent aphasia, regardless of the underlying neuropathological features. Considerable progress has been made in recent years in our understanding of the ...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-007-0241-6
更新日期:2007-07-01 00:00:00
abstract::This report presents the largest series of consecutive, neuropathologically confirmed cases of frontotemporal degeneration (FTD). Prior studies have found dementia lacking distinctive histology (DLDH) to be the most common pathology underlying the clinical diagnosis of FTD. In this series of 76 cases, 29 (38%) were fo...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-004-0900-9
更新日期:2004-11-01 00:00:00
abstract::The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to s...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-013-1161-2
更新日期:2013-10-01 00:00:00
abstract::This study was undertaken to elucidate, using the Golgi method, the neuropathological change in the brain of the macular mutant mouse, whose hemizygote (Ml/y) is considered to be a model of Menkes kinky hair disease (MKHD). The hemizygote mice gradually lost weight after 10 days of age and died with emaciation and sei...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687266
更新日期:1987-01-01 00:00:00
abstract::Focal cerebral ischemia was induced by occlusion of the right middle cerebral artery in hypoglycemic, normoglycemic, as well as in acute and chronic diabetic rats. The brain damage was studied after 4 days. The volume of infarction was decreased in hypoglycemia (29 +/- 19 mm3 (mean +/- SD) versus 58 +/- 35 mm3, P less...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00693778
更新日期:1987-01-01 00:00:00
abstract::New pericapillary inclusion bodies were found in 17 cases of sporadic amyotrophic lateral sclerosis (ALS). The inclusion bodies consisted of paracrystalline arrays with 5-7 nm electron-dense subunits, were discernible with the light microscope and had the staining properties of protein. They were surrounded by capilla...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00687970
更新日期:1986-01-01 00:00:00
abstract::A mixed lymphoblastic T cell lymphoma and gonadotroph cell pituitary adenoma occurred 25 years after first resection of the adenoma. Within 1 year the lymphoma overgrew the adenoma, but was still restricted to the sellar region. Histologically, lymphoma and adenoma components were tightly admixed. Possible pathogeneti...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s004010050990
更新日期:1999-03-01 00:00:00
abstract::The choroid plexus is an epithelial-endothelial vascular convolute within the ventricular system of the vertebrate brain. It consists of epithelial cells, fenestrated blood vessels, and the stroma, dependent on various physiological or pathological conditions, which may contain fibroblasts, mast cells, macrophages, gr...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-009-0627-8
更新日期:2010-01-01 00:00:00
abstract::A 25-year-old homosexual AIDS patient presented with progressive cognitive, motor and behavioral disturbances consistent with HIV encephalopathy. CT scans demonstrated progressive diffuse brain atrophy. Neuropathology showed predominant cortical changes including severe neuronal loss corroborated by morphometry. Only ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00294450
更新日期:1991-01-01 00:00:00
abstract::The binding of carbon disulphide sulphur was studied in the spinal cord and its axons of four control and four phenobarbitone pretreated adult rats 3 and 6 h after an intraperitoneal injection of 650 mumol of CS2 in olive oil. The binding of CS2 carbon was measured in the same fractions of two adult control rats 4.5 h...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00685369
更新日期:1976-11-15 00:00:00
abstract::Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-015-1406-3
更新日期:2015-05-01 00:00:00
abstract::Progression of neuritic dystrophy is a histological hallmark of Alzheimer's disease (AD) in addition to amyloid deposition and neurofibrillary tangle formation. Dystrophic neurites (DNs) are abnormal neurites, and are closely associated with amyloid deposits. To clarify the process of DN formation, we immunohistochemi...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-004-0907-2
更新日期:2004-11-01 00:00:00
abstract::This report illustrates a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) masquerading as neurofibromatosis due to multifocal enlargements of spinal nerve roots. The patient initially complained of intermittent numbness of the hands and leg weakness at age 62. Nerve conduction velocities were ...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-002-0616-7
更新日期:2003-02-01 00:00:00
abstract::The ultrastructure of the nervous tissue in a benign ovarian teratoma is described. This tissue was organized into areas having both "meningeal" and "ependymal" surfaces, between which were found astrocytes, ependymal cells, neurones with synapses and microglia. These cells all had ultrastructural similarities to thei...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00686623
更新日期:1987-01-01 00:00:00
abstract::The intracellular localization of myoglobin(Mb) mRNA in the skeletal muscles of normal subjects and patients with Duchenne muscular dystrophy(DMD) or amyotrophic lateral sclerosis(ALS) was examined by in situ hybridization using a biotin-labeled cDNA probe. In cross sections of normal muscles, Mb mRNA signals were dem...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00369442
更新日期:1993-01-01 00:00:00
abstract::Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In t...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-008-0411-1
更新日期:2008-09-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product...
journal_title:Acta neuropathologica
pub_type: 杂志文章,评审
doi:10.1007/s00401-013-1125-6
更新日期:2013-06-01 00:00:00
abstract::Accumulation of mitochondrial DNA (mtDNA) deletions has been proposed to be responsible for the presence of respiratory-deficient neurons in several CNS diseases. Deletions are thought to originate from double-strand breaks due to attack of reactive oxygen species (ROS) of putative inflammatory origin. In epileptogene...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-016-1561-1
更新日期:2016-08-01 00:00:00
abstract::Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PS...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-020-02158-2
更新日期:2020-08-01 00:00:00
abstract::Methylmercury (MeHg) poisoning (20 mg/kg body weight) in embryonic mice resulted in significant reductions of mitotic indices in the neuroepithelial germinal cells of the telencephalon at the ventricular surface 4 to 12 h following intoxication. After 24 h, no significant difference in the mitotic indices was observed...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00293454
更新日期:1991-01-01 00:00:00
abstract::Data on the dural invasiveness of pituitary adenomas have been correlated to the expression of matrix metalloproteinases (e.g. MMP-9). Serine proteases have not yet been investigated in human pituitary adenomas. In this study, paraffin-embedded material from 84 human pituitary adenomas (acromegaly n=18, Cushing's dise...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/s00401-003-0747-5
更新日期:2003-11-01 00:00:00
abstract::Foetal rat brain reaggregate cultures have been employed to investigate the morphological changes associated with the neurotoxic action of ethylcholine mustard aziridinium (ECMA). In a companion study we provided evidence for apparent selective cholinergic neurotoxicity. Exposure of 9-day-old cultures to 12.5 microM E...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00334882
更新日期:1993-01-01 00:00:00
abstract::A woman of 22 years developed heavy pain in the neck and arms with weakness and paresthesia. She died two days after a myelography which was normal. At autopsy an enterogenous extra- and intra-medullary cyst of the cervical cord (C3, C4) was found. In addition the cervical cord apart from the cyst and the uppermost th...
journal_title:Acta neuropathologica
pub_type: 杂志文章
doi:10.1007/BF00691967
更新日期:1977-11-28 00:00:00