Gamma‐synuclein pathology in amyotrophic lateral sclerosis

Abstract

ObjectiveThe prominent histopathological feature of the amyotrophic lateral sclerosis (ALS) is the presence of intracellular inclusions in degenerating neurons and their axons. The appearance and localization of these pathological structures depend on an aggregated protein that forms their scaffold. We investigated if γ-synuclein, an aggregation-prone protein highly expressed in healthy motor neurons, and predominantly localized in their axons and synaptic terminals is involved in ALS pathology.MethodsImmunostaining of histological sections and sequential protein extraction from postmortem neural samples followed by immunoblotting.ResultsImmunohistochemical screening revealed a subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel type of pathology characterized by the accumulation of γ-synuclein in distinct profiles within the dorsolateral column. Sequential fractionation of proteins from the spinal cord tissues revealed detergent-insoluble γ-synuclein species specifically in the dorsolateral corticospinal tracts of a ALS patient with γ-synuclein-positive profiles in this region. These profiles are negative for protein markers commonly found in pathological inclusions in the spinal cord of ALS patients and most probably represent degenerated axons of upper motor neurons that have lost their neurofilaments. A subset of these profiles was found in association with phagocytic cells positive for Mac-2/Galectin-3. A smaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusions in the cell body of remaining spinal motor neurons.InterpretationOur observations suggest that pathological aggregation of γ-synuclein might contribute to the pathogenesis of ALS.

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

“…A number of novel proteins were implicated in neuronal death: Increased levels of leucine‐rich repeat‐containing protein 50 were identified within C‐boutons of motor neurons, implicating cholinergic transmission in disease pathogenesis, 50 and conotoxin‐like protein (CTXLP), a novel ERVK protein, was associated with upper motor neuron degeneration 72 . γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis 73 . While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations 51,74 .…”

“… 72 γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis. 73 While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations. 51 , 74 Finally, brain tissue was used to confirm that a small proportion of patients who develop sporadic FTD have fused in sarcoma (FUS) pathology which has also been observed in rare familial ALS cases due to a mutation in the FUS gene.…”

“…For example, DPR proteins, a signature of C9orf72 related disease, point to unique pathological mechanisms in those who carry this mutation 51 . Other studies have suggested that a more diverse pathological onslaught is occurring in ALS; for example, pathology within glial cells 76 and the presence of γ ‐synuclein 73 are both reported. These results may explain why targeting single disease mechanisms has thus far resulted in disappointing clinical trial outcomes 99 .…”

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

“…A number of novel proteins were implicated in neuronal death: Increased levels of leucine‐rich repeat‐containing protein 50 were identified within C‐boutons of motor neurons, implicating cholinergic transmission in disease pathogenesis, 50 and conotoxin‐like protein (CTXLP), a novel ERVK protein, was associated with upper motor neuron degeneration 72 . γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis 73 . While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations 51,74 .…”

“… 72 γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis. 73 While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations. 51 , 74 Finally, brain tissue was used to confirm that a small proportion of patients who develop sporadic FTD have fused in sarcoma (FUS) pathology which has also been observed in rare familial ALS cases due to a mutation in the FUS gene.…”

“…For example, DPR proteins, a signature of C9orf72 related disease, point to unique pathological mechanisms in those who carry this mutation 51 . Other studies have suggested that a more diverse pathological onslaught is occurring in ALS; for example, pathology within glial cells 76 and the presence of γ ‐synuclein 73 are both reported. These results may explain why targeting single disease mechanisms has thus far resulted in disappointing clinical trial outcomes 99 .…”

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

“…The increased expression of γ-synuclein in basal ganglia from Vps13a −/− mice is of specific note since mice genetically over-expressing γ-synuclein display an age-dependent neurodegeneration, abnormal psycho-emotional status and motor deficiency [ 47 ]. Increased levels of γ-synuclein have been reported in cerebrospinal fluid in Alzheimer disease (AD) patients, in individuals with Creutzfeld-Jakob disease [ 48 ], and may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) [ 52 ]. We then asked whether the increase cellular levels of γ-synuclein might be associated with the accumulation of other neurotoxic proteins such as neuronal microtubule-associated protein tau, which organizes into pathogenic fibrils in phosphorylated form.…”

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration

“…The expression level of SNCG has been correlated with the progression of some cancers [31] and Alzheimer's disease [32], suggesting a role in the pathophysiology. Aggregated SNCG was found in the motor neurons of some amyotrophic lateral sclerosis (ALS) patients [33]. In addition, SNCG immunopositive glial inclusions appeared in the optic nerve of glaucoma patients [34].…”

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

“…A number of novel proteins were implicated in neuronal death: Increased levels of leucine‐rich repeat‐containing protein 50 were identified within C‐boutons of motor neurons, implicating cholinergic transmission in disease pathogenesis, 50 and conotoxin‐like protein (CTXLP), a novel ERVK protein, was associated with upper motor neuron degeneration 72 . γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis 73 . While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations 51,74 .…”

“… 72 γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis. 73 While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations. 51 , 74 Finally, brain tissue was used to confirm that a small proportion of patients who develop sporadic FTD have fused in sarcoma (FUS) pathology which has also been observed in rare familial ALS cases due to a mutation in the FUS gene.…”

“…For example, DPR proteins, a signature of C9orf72 related disease, point to unique pathological mechanisms in those who carry this mutation 51 . Other studies have suggested that a more diverse pathological onslaught is occurring in ALS; for example, pathology within glial cells 76 and the presence of γ ‐synuclein 73 are both reported. These results may explain why targeting single disease mechanisms has thus far resulted in disappointing clinical trial outcomes 99 .…”

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

“…The increased expression of γ-synuclein in basal ganglia from Vps13a −/− mice is of specific note since mice genetically over-expressing γ-synuclein display an age-dependent neurodegeneration, abnormal psycho-emotional status and motor deficiency [ 47 ]. Increased levels of γ-synuclein have been reported in cerebrospinal fluid in Alzheimer disease (AD) patients, in individuals with Creutzfeld-Jakob disease [ 48 ], and may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) [ 52 ]. We then asked whether the increase cellular levels of γ-synuclein might be associated with the accumulation of other neurotoxic proteins such as neuronal microtubule-associated protein tau, which organizes into pathogenic fibrils in phosphorylated form.…”

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration

“…The expression level of SNCG has been correlated with the progression of some cancers [31] and Alzheimer's disease [32], suggesting a role in the pathophysiology. Aggregated SNCG was found in the motor neurons of some amyotrophic lateral sclerosis (ALS) patients [33]. In addition, SNCG immunopositive glial inclusions appeared in the optic nerve of glaucoma patients [34].…”

The contribution of brain banks to knowledge discovery in amyotrophic lateral sclerosis: A systematic review

“…A number of novel proteins were implicated in neuronal death: Increased levels of leucine‐rich repeat‐containing protein 50 were identified within C‐boutons of motor neurons, implicating cholinergic transmission in disease pathogenesis, 50 and conotoxin‐like protein (CTXLP), a novel ERVK protein, was associated with upper motor neuron degeneration 72 . γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis 73 . While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations 51,74 .…”

“… 72 γ ‐synuclein was identified within the dorsolateral column in ALS patients and has been speculated to have a role in disease pathogenesis. 73 While p62 inclusions can occur in ALS and FTD phenotypes, DPR proteins are particularly specific to ALS‐FTD patients and are highly predictive of C9orf72 mutations. 51 , 74 Finally, brain tissue was used to confirm that a small proportion of patients who develop sporadic FTD have fused in sarcoma (FUS) pathology which has also been observed in rare familial ALS cases due to a mutation in the FUS gene.…”

“…For example, DPR proteins, a signature of C9orf72 related disease, point to unique pathological mechanisms in those who carry this mutation 51 . Other studies have suggested that a more diverse pathological onslaught is occurring in ALS; for example, pathology within glial cells 76 and the presence of γ ‐synuclein 73 are both reported. These results may explain why targeting single disease mechanisms has thus far resulted in disappointing clinical trial outcomes 99 .…”

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis

“…The increased expression of γ-synuclein in basal ganglia from Vps13a −/− mice is of specific note since mice genetically over-expressing γ-synuclein display an age-dependent neurodegeneration, abnormal psycho-emotional status and motor deficiency [ 47 ]. Increased levels of γ-synuclein have been reported in cerebrospinal fluid in Alzheimer disease (AD) patients, in individuals with Creutzfeld-Jakob disease [ 48 ], and may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) [ 52 ]. We then asked whether the increase cellular levels of γ-synuclein might be associated with the accumulation of other neurotoxic proteins such as neuronal microtubule-associated protein tau, which organizes into pathogenic fibrils in phosphorylated form.…”

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration

“…The expression level of SNCG has been correlated with the progression of some cancers [31] and Alzheimer's disease [32], suggesting a role in the pathophysiology. Aggregated SNCG was found in the motor neurons of some amyotrophic lateral sclerosis (ALS) patients [33]. In addition, SNCG immunopositive glial inclusions appeared in the optic nerve of glaucoma patients [34].…”