Forebrain overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA Experimental Neurology
(Impact Factor: 4.7).
01/2010; 221(1):86-97. DOI: 10.1016/j.expneurol.2009.10.005
Transgenic (Tg) mouse models of Parkinson's disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (α-syn) to recapitulate PD-like motor impairments as well as PD-like nigrostriatal degeneration and α-syn pathology. However, cognitive impairments and cortical α-syn pathology are also common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant α-syn. Here we show that both WT and A53T mutant α-syn lead to massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development, with hippocampal synapse loss as evidenced by reduced levels of pre- and postsynaptic markers. However, when mutant and WT α-syn expression was repressed until the Tg mice were mature postnatally and then induced for several months, no hippocampal neuron loss was observed. These data imply that developing neurons are more vulnerable to degenerate than mature neurons as a consequence of forebrain WT and mutant α-syn overexpression.
Available from: Davide Amato
- " and a rapid progressive dopaminergic phenotype ( Sekine et al . , 2010 ) . In animal mouse brain , the detected high levels of - synuclein led to conversion into insolubility and / or small inclusion formations in vivo ( Masliah et al . , 2000 ; Giasson et al . , 2002 ; Kahle et al . , 2001 ; Neumann et al . , 2002 ; Gomez - Isla et al . , 2003 ; Lim et al . , 2010 ) . By demonstrating strong and age - related increase of insol - uble full - length - synuclein in dopaminergic synapse - rich striatum of BAC - synuclein transgenic rats comparable with different se - verity of human Parkinson ' s disease , we provide evidence that the conversion and deposition of - synuclein is related to pathology o"
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ABSTRACT: Conversion of soluble α-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of α-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the α-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type α-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent α-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated α-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.
Brain 02/2013; 136(Pt 2):412-32. DOI:10.1093/brain/aws358 · 9.20 Impact Factor
Available from: lib.jncasr.ac.in
- "Exogenous over-expression of wild type and mutant α-synuclein in cell types ranging from yeast to humans causes a range of cellular impairments, including multiple trafficking defects (Cooper et al., 2006; Thayanidhi et al., 2010; Soper et al., 2011), mitochondrial degeneration (Martin et al., 2006; Schapira, 2008), oxidative stress (Junn and Mouradian, 2002; Esteves et al., 2009) and defective lipid/sterol metabolism (Bras et al., 2008). In vivo, transgenic over-expression of α-synuclein in mouse affects neurotransmitter release (Nemani et al., 2010), and causes neuronal death and degeneration, as well as motor deficits (Yamada et al., 2004; Dalfó et al., 2004b; Yazawa et al., 2005; Lim et al., 2010; Siebert et al., 2010; Stemberger et al., 2010) that recapitulate to some degree the pathological conditions of human synucleinopathies. Not surprisingly, these pathologies could be attenuated somewhat by the enhancement of autophagic clearance of cellular aggregates (Spencer et al., 2009), thus confirming that synuclein aggregates are a major contributing factor to these conditions. "
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ABSTRACT: Neuronal dysfunctions and neurodegeneration are often associated with defects in membrane transport. Synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathological feature--insoluble aggregates composed largely of the protein α-synuclein in certain populations of neurons and glia. The actual physiological function of the brain-enriched α-synuclein is still not particularly clear. What is obvious is that when the protein is present in pathologically high amounts, or in mutant forms with enhanced membrane association and oligomerization, it causes neuronal demise with manifestations of impaired neuronal traffic, heightened oxidative stress, mitochondrial degeneration and defects in lipid metabolism. α-synuclein's direct association with the activities of key components of the eukaryotic membrane traffic machinery, namely Rabs and the soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs), has highlighted a key role for membrane transport defects in α-synuclein-mediated pathology. Here, we summarize and discuss recent findings in this regard, and their implications in the molecular aspects of synucleinopathy.
Brain Research Reviews 03/2011; 67(1-2):268-81. DOI:10.1016/j.brainresrev.2011.03.002 · 5.93 Impact Factor
Principles of Medical Biology 01/1997; 8:933-949. DOI:10.1016/S1569-2582(97)80108-0
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