Sabeen A. Kazmi's research while affiliated with The Neurosciences Institute and other places

Publications (6)

Article
Full-text available
Multiple system atrophy (MSA), a progressive neurodegenerative disease characterized by autonomic dysfunction and motor impairment, is caused by the self-templated misfolding of the protein α-synuclein. With no treatment currently available, we sought to characterize the spread of α-synuclein in a transgenic mouse model of MSA prion propagation to...
Article
Full-text available
Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/−, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our stud...
Article
Full-text available
In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83+/−), inducing neurological disease following intracranial inocul...
Article
In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions rob...
Article
Importance Accumulation of the protein tau is a defining characteristic of several neurodegenerative diseases. Thorough assessment of transgenic (Tg) mouse lines that replicate this process is critical for establishing the models used for testing anti-tau therapeutics in vivo. Objective To define a consistent mouse model of disease for use in futu...
Article
Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are l...

Citations

... The expression of human αSyn in the CNS of both of these mouse lines is comparable, with slightly higher expression in TgM20 +/− mice [24]. While previous studies have examined the transmission of neurological disease from MSA brain extracts into TgM83 +/− mice [61,78,87,88], these studies either did not analyze comparative host-induced, strain specificity, or were unable to induce αSyn pathology in mouse lines expressing WT human αSyn. Our data suggests that the primary amino acid sequence of αSyn expressed by the host, plays a conspicuous role in the regional distribution, cellular tropism, and, importantly, severity of the neurological disease. ...
... Our study demonstrated that αSyn-MSA is the most potent of the selected synucleinopathy-derived proteoforms, inducing widespread αSyn pathology. This finding is consistent with the kinetics of MSA-derived αSyn, illustrated in numerous seeding studies [6,13,59,78,83,[86][87][88]; αSyn-MSA characteristically exhibits aggressive rates of pathological propagation, a property reminiscent of the more rapid progression of disease in patients with MSA [20,27]. Analysis of the regional distribution of induced αSyn pathology revealed that MSA-injection resulted in a dramatically diverse pathological distribution in TgM20 +/− compared to TgM83 +/− mice, with the latter exhibiting significant hindbrain and minimal hippocampal affliction (Figs. 4, 5; Supplementary Fig. 7c, online resource). ...
... Primary antibody, EP1536Y. (Data published in [106].) c MSA propagation in HEK293T cells expressing various α-synuclein-YFP substrates (data published in [108]). ...
... An attempt at recreating the rTg4510 mice is the rT2/ T2 mouse line that develops tau inclusions by 5-7 months, but has 17X overexpression and has much slower onset of pathology 58 . An alternative model is the PS19 mice that are excellent for tau seeding experiments 59,60 ; however, the inconsistency in the onset of tau pathology, ranging from 6 to 12 months, makes it difficult to assess tau-inclusion progression and potential therapeutic effects in that model 59,61 . PS19 mice also present major sex differences where females have a 5-6month delay in pathology 62 , making it difficult to include both sexes in studies. ...
... Analysis of the regional distribution of induced αSyn pathology revealed that MSA-injection resulted in a dramatically diverse pathological distribution in TgM20 +/− compared to TgM83 +/− mice, with the latter exhibiting significant hindbrain and minimal hippocampal affliction (Figs. 4, 5; Supplementary Fig. 7c, online resource). This is interesting, as MSA seeding studies using TgM83 +/− mice have consistently noted this hindbrain preference of MSA-induced pathology, regardless of inoculation route (intraglossal, intraperitoneal, intracerebral or intramuscular) or inoculation site [13,45,50,60,61,68,78,85,87], and have consequentially concluded that this regional tropism is determined by the MSA-derived αSyn strain. However, our results argue that regional selectivity is determined by an interaction between strain and substrate properties, as αSyn-MSA injection into TgM20 +/mice resulted in αSyn pathology in the hippocampus and ventral cortex regions, with the hindbrain and spinal cord less affected (Supplementary Fig. 7c, online resource). ...
... As well as a distinctive conformation, CTE p-tau aggregates also contain a yet unknown hydrophobic non-proteinaceous cofactor. Importantly, even though the p-tau in CTE is a distinct molecule from other tauopathies, it has been shown to have the same prion-like properties of infection and self-propagation as the p-tau in AD (16,17). ...