Mechanisms of DiseaseAssociation between conformational mutations in neuroserpin and onset and severity of dementia
Introduction
Neuronal or perineuronal protein aggregates are a characteristic feature of the common dementias,1, 2 as with the deposits of β-amyloid in Alzheimer's disease and prion protein in the spongiform encephalopathies. In sporadic and familial Parkinson's disease, α-synuclein accumulates within neurons to form discrete Lewy bodies;3 similarly, Pick bodies of aggregated tau protein are present in some forms of familial frontotemporal dementia.4 A further type of neuronal inclusion, the collins body, has also been found in association with familial neurodegenerative disease.5, 6, 7 The particular importance of this finding is that Collins bodies are formed of aggregated neuroserpin, a neuron-specific protease inhibitor8, 9 that is closely related in structure10 to the well studied plasma protease inhibitor α1-antitrypsin—another serpin.11 In particular, the mutations causing the aggregation of neuroserpin were found to be homologous to mutations known to cause the aggregation of α1-antitrypsin in hepatocytes.12, 13 This aggregation of α1-antitrypsin, and not its accompanying deficiency, is responsible for hepatocyte damage and the eventual development of cirrhosis. The identification of the same type of polymeric linkage in neuroserpin indicates a shared molecular pathophysiology in the associated neurodegenerative and cirrhotic processes.14 Each disease arises from the same destabilising mutations,15 and polymerisation of the conformationally unstable protein occurs intracellularly at the site of synthesis to give a cumulative loss over time of hepatocytes with aggregates of α1-antitrypsin, and of neurons with aggregates of neuroserpin.
These findings highlight a disputed question: is the formation of protein aggregates an incidental feature of the dementias or is it a causative factor? Are the neuronal Lewy bodies, Pick bodies, and amyloid plaques just histological markers or are they the cause of the neurodegeneration? To answer this question, we investigated five families with different clinical presentations of familial encephalopathies with neuroserpin inclusion bodies (FENIB).
Section snippets
Participating families
Families were selected after a literature search and from referred families, the criteria for selection being the presence of Collins bodies together with the availability of brain tissue for further investigation. Probands from five families with histories of neurodegenerative disease (panel 1) were assessed. Tissue was available from autopsy in three of these (cases 1, 2, and 3), and from brain biopsies in two others (cases 4 and 5).
Procedures
Brain-tissue specimens were fixed in formalin, embedded in
Results
Immunostaining revealed that Collins bodies in the probands from each family assessed contained neuroserpin. This finding was further confirmed in case 3 by isolation of inclusions from paraffin-embedded brain tissue sections by laser-capture microscopy. SDS-PAGE of the solubilised inclusions showed a single band on silver-stained gels, identified as neuroserpin by Western blot analysis. All cases were heterozygous for mutations resulting in aminoacid substitutions in neuroserpin. The mutations
Discussion
The concept of the conformational diseases28 was initially based on the aggregation of α1-antitrypsin, which results in progressive hepatocellular damage and the eventual development of cirrhosis.12, 13 An accompanying prediction28 was that a similar process would explain the slow development and late onset of inclusion-body neurodegenerative diseases. This prediction was confirmed with the finding5 of two families with dementia due to mutations in neuroserpin, a brain-specific protein8, 9
GLOSSARY
- collins bodies
- Characteristic eosinophilic inclusion bodies positive by periodic-acid-Schiff staining and resistant to diastase, formed by the aggregation of neuroserpin within the endoplasmic reticulum of neurons.
- neuroserpin
- A brain-specific serpin synthesised and secreted by neurons, particularly during their growth.
- progressive myoclonus epilepsy (PME)
- Progressive neurological deterioration characterised by myoclonus, tonic-clonic seizures, cerebellar ataxia, and dementia.
- serpins
- A family of
References (33)
- et al.
Aggregates in neurodegenerative disease: crowds and power?
Neurosci
(1999) - et al.
The cerebral proteopathies
Neurobiol Aging
(2000) - et al.
Familial encephalopathy with neuroserpin inclusions bodies
Am J Pathol
(1999) - et al.
Biochemical characterization of a neuroserpin variant associated with hereditary dementia
Am J Pathol
(2001) - et al.
Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons: implications for the regulation of motor learning and neuronal survival
J Biol Chem
(1997) - et al.
Crystal structure of neuroserpin: a neuronal serpin involved in a conformational disease
FEBS Lett
(2001) - et al.
The serpins are an expanding superfamily of structurally similar but functionally diverse proteins: evolution, mechanism of inhibition, novel functions, and a revised nomenclature
J Biol Chem
(2001) - et al.
α1-antitrypsin Siiyama (Ser53→Phe); further evidence for intracellular loop-sheet polymerisation
J Biol Chem
(1993) - et al.
Conformational changes in serpins, 1: the native and cleaved conformations of alpha(1)-antitrypsin
J Mol Biol
(2000) - et al.
Mutant neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro
J Biol Chem
(2002)
The native strains in the hydrophobic core and flexible reactive loop of a serine protease inhibitor: crystal structure of an uncleaved alpha1-antitrypsin at 2.7 Å
Structure
Antithrombin-Gly 424 Arg: a novel point mutation responsible for type 1 antithrombin deficiency and neonatal thrombosis
Blood
Conformational diseases
Lancet
Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease
Science
Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits
J Neuropathol Exp Neurol
Familial dementia caused by polymerisation of mutant neuroserpin
Nature
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