Transactivation response DNA-binding protein of 43 kDa proteinopathy and lysosomal abnormalities in spastic paraplegia type 11.
Shinichiro MoriHiroyuki HondaHideomi HamasakiNaokazu SasagasakoSatoshi O SuzukiHirokazu FuruyaTakayuki TaniwakiToru IwakiPublished in: Neuropathology : official journal of the Japanese Society of Neuropathology (2021)
Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11.
Keyphrases
- amyotrophic lateral sclerosis
- cerebral palsy
- spinal cord
- intellectual disability
- binding protein
- botulinum toxin
- neuropathic pain
- upper limb
- end stage renal disease
- induced apoptosis
- autism spectrum disorder
- oxidative stress
- endoplasmic reticulum stress
- cell death
- spinal cord injury
- ejection fraction
- chronic kidney disease
- newly diagnosed
- signaling pathway
- cell free
- single cell
- cerebral ischemia
- heat shock protein
- circulating tumor
- single molecule
- peritoneal dialysis
- parkinson disease
- living cells
- fluorescent probe
- cerebrospinal fluid
- prognostic factors
- genome wide
- pet imaging
- low grade
- small molecule
- amino acid
- dna methylation
- drug induced
- deep brain stimulation
- resting state
- functional connectivity
- computed tomography