Generalization of the Prion Hypothesis to Other Neurodegenerative Diseases: An Imperfect Fit

Guest, Will; Silverman, Judith M.; Pokrishevsky, Edward; O'Neill, Megan A.; Grad, Leslie I.; Cashman, Neil R.

doi:10.1080/15287394.2011.618967

Cited by 66 publications

(60 citation statements)

References 167 publications

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“…Increasing evidence supports the notion that progression of pathology in neurodegenerative diseases such as AD, Parkinson disease, tauopathies, and Huntington disease is a result of propagation of misfolded or aggregated proteins (6,7,16). The capability of a pathogenic protein conformation to self-propagate is the central tenant of the prion hypothesis, with a necessary requirement of sporadic prion diseases being that the process of conformational conversion must be capable of being mediated by the unmutated WT PrP.…”

Section: Discussionmentioning

confidence: 98%

“…One of the mechanisms by which a mutant or wild-type (WT) protein can dominate pathogenesis of phenotypically diverse diseases is by propagated protein misfolding, such as that underpinning the prion diseases, which has been increasingly implicated in other neurodegenerative and systemic disorders (6,7). A role for propagated protein misfolding in ALS is supported by the prion-like spatiotemporal progression of disease through the neuroaxis (8,9).…”

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Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Grad

Yerbury

Turner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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371

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Amyotrophic lateral sclerosis (ALS) is predominantly sporadic, but associated with heritable genetic mutations in 5-10% of cases, including those in Cu/Zn superoxide dismutase (SOD1). We previously showed that misfolding of SOD1 can be transmitted to endogenous human wild-type SOD1 (HuWtSOD1) in an intracellular compartment. Using NSC-34 motor neuron-like cells, we now demonstrate that misfolded mutant and HuWtSOD1 can traverse between cells via two nonexclusive mechanisms: protein aggregates released from dying cells and taken up by macropinocytosis, and exosomes secreted from living cells. Furthermore, once HuWt-SOD1 propagation has been established, misfolding of HuWt-SOD1 can be efficiently and repeatedly propagated between HEK293 cell cultures via conditioned media over multiple passages, and to cultured mouse primary spinal cord cells transgenically expressing HuWtSOD1, but not to cells derived from nontransgenic littermates. Conditioned media transmission of HuWtSOD1 misfolding in HEK293 cells is blocked by HuWtSOD1 siRNA knockdown, consistent with human SOD1 being a substrate for conversion, and attenuated by ultracentrifugation or incubation with SOD1 misfolding-specific antibodies, indicating a relatively massive transmission particle which possesses antibody-accessible SOD1. Finally, misfolded and protease-sensitive HuWtSOD1 comprises up to 4% of total SOD1 in spinal cords of patients with sporadic ALS (SALS). Propagation of HuWtSOD1 misfolding, and its subsequent cell-tocell transmission, is thus a candidate process for the molecular pathogenesis of SALS, which may provide novel treatment and biomarker targets for this devastating disease.A myotrophic lateral sclerosis (ALS) is a fatal neuromuscular condition that afflicts as many as 1 of 350 males and 420 females over the age of 18 (1). In ALS, degeneration of upper and lower motor neurons causes progressive muscle paralysis and spasticity, affecting mobility, speech, swallowing, and respiration (2). Half of affected individuals die within 3 y, and less than 20% survive for more than 5 y (3); 90-95% of ALS cases are sporadic (SALS) in which some apparently facilitating gene mutations, such as repeat expansions in the gene that encodes ataxin-2 (4), have been identified. The remaining 5-10% of ALS cases are familial (FALS) and predominantly associated with Mendelian-inherited mutations in the genes encoding Cu/Zn superoxide dismutase (SOD1), TAR-DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/ TLS), C9ORF72, and other genes (reviewed in ref. 3).Despite the profusion of functionally diverse genes implicated in FALS and SALS, clinical and pathological similarities between all forms of ALS suggest the existence of a common pathogenic pathway that could be united by a single gene/protein (5). One of the mechanisms by which a mutant or wild-type (WT) protein can dominate pathogenesis of phenotypically diverse diseases is by propagated protein misfolding, such as that underpinning the prion diseases, which has been increa...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Grad

Yerbury

Turner

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

371

397

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“…Comparable to prion diseases, in which the pathological prion protein propagates by a seeding/nucleation polymerization process and is transferred from cell to cell, stereotypic spread has been observed in e.g. synucleopathies and Alzheimer's disease [21][22][23][24]. For in vitro and in vivo studies and especially for the examination of the neuropathologically characteristic misfolded, oligomerized and aggregated proteins discrimination between normal and aberrant forms is essential.…”

Section: Discussionmentioning

confidence: 99%

Protease-resistant SOD1 aggregates in amyotrophic lateral sclerosis demonstrated by Paraffin Embedded Tissue (PET) blot

Steinacker

Berner

Thal

et al. 2014

Acta Neuropathologica Communications

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Objectives: The paraffin-embedded tissue (PET) blot technique followed by limited protease digestion has been established to detect protein aggregates in prion diseases, alpha-synucleopathies, and tauopathies. We analyzed whether the scope of the method can be extended to analyze aggregates in mouse and human tissue with amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutation.Methods: Formalin-fixed and paraffin-embedded brain and spinal cord tissue from SOD1 G93A mice was first analyzed for the expression of SOD1, aggregated SOD1, ubiquitin, and p62 by convential immunohistochemistry and then used to establish the PET blot technique, limited protease digest, and immunodetection of SOD1 aggregates. The method was then transferred to spinal cord from an ALS patient with SOD1 E100G mutation.Results: Mouse and human paraffin-embedded brain and spinal cord tissue can be blotted to membranes and stained with anti-SOD1 antibodies. The SOD1 labelling is abolished after limited proteolytic digest in controls, whereas under identical conditions SOD1 aggregates are detected the SOD1 G93A mouse model of ALS and in human familial ALS. The most prominent areas where aggregates could be detected are the brainstem and the anterior horn of the spinal cord.Discussion: Applicability of the PET blot technique to demonstrate SOD1 aggregates in ALS tissue associated with mutations in the SOD1 gene offers a new approach to examine potential spreading of aggregates in the course of ALS.

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“…It is conceivable that, under these circumstances and possibly only for a short time, soluble aggregates of misfolded and hyperphosphorylated but nonfibrillar tau protein penetrate as far as the terminal branches of the axon and into presynaptic terminals, where they then become available for transport to the postsynaptic side of the synaptic cleft (Braak and Del Tredici 2015b). Were that to prove true, the pathological process would be transmissible to the successive neurons only via terminal axons and synaptic connections of involved nerve cells.These considerations and experimental data make it possible to associate the AD-and PD- (Prusiner 1982(Prusiner , 2012(Prusiner , 2013McBride et al 2001;Vella et al 2007;Aguzzi and Calella 2009;Aguzzi and Rajendran 2009;Guest et al 2011;Liberski 2012;Herva and Spillantini 2015). However, we prefer to use the term "prion-like" to differentiate sporadic AD and PD from rapidly progressive and infectious prion diseases, as PD and AD have not been shown to be rapidly progressive and contagious (Olanow and McNaught 2011;Iba 2013;Irwin et al 2013;Kaufman and Diamond 2013;Beekes et al 2014;Goedert et al 2014Goedert et al , 2015Brandel et al 2015;Walker and Jucker 2015;Walsh and Selkoe 2016).…”

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confidence: 99%

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

105

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Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

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Generalization of the Prion Hypothesis to Other Neurodegenerative Diseases: An Imperfect Fit

Cited by 66 publications

References 167 publications

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

Protease-resistant SOD1 aggregates in amyotrophic lateral sclerosis demonstrated by Paraffin Embedded Tissue (PET) blot

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

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