Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death in the dopaminergic system and abnormal protein ...

Filamentous inclusions made of ?-synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in ?-synuclein. We report here the assembly properties and secondary ...

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the ?-synuclein (?-Syn) A53T mutant mouse. Elevated levels of ?-Syn were ...

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the ?-synuclein (?-Syn) A53T mutant mouse. Elevated levels of ?-Syn were ...

The aggregation of {alpha}-synuclein is a hallmark feature of Parkinson's disease (PD) and other synucleinopathies. Metals are the significant etiological factors in PD, and their interaction with {alpha}-synuclein affect dramatically the kinetics of fibrillation in vitro and are proposed to play an important and potential neurodegenerative role in vivo. In the present study, we ...

Parkinson disease is characterized by the accumulation of aggregated ?-synuclein as the major component of the Lewy bodies. ?-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that ...

Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is ...

Alpha-synuclein is the major protein component of Lewy bodies, a cardinal pathological feature of the degenerating Parkinsonian brain. Alpha-synuclein has been reported to be able to intercalate into membranes via formation of an alpha-helical structure at its N-terminal end. Recent in vitro studies from various laboratories have demonstrated that ?-synuclein can physically associate with ...

SummaryMutations in ?-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson�s disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although over-expression of LRRK2 alone did not cause neurodegeneration, the presence of ...

We identified three S. cerevisiae lipid elongase null mutants (elo1?, elo2?, and elo3?) that enhance the toxicity of alpha-synuclein (?-syn). These elongases function in the endoplasmic reticulum (ER) to catalyze the elongation of medium chain fatty acids to very long chain fatty acids, which is a component of sphingolipids. Without ?-syn expression, the various elo ...

There is a growing interest in the potential roles of misfolded protein interactions in neurodegeneration. To investigate this issue, we inoculated 3 prion strains intracerebrally into transgenic (TgM83) mice that overexpress human A53T ?-synuclein. In comparison to nontransgenic controls, there was a striking decrease in the ...

Parkinson's disease (PD) is characterized by the polymerization of wild-type (WT) or mutant alpha-synuclein (AS) into aggregates and fibrils, which are observed as Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients. However, inability to demonstrate aggregation in many cell culture systems is a major drawback for effective in vitro modeling of AS aggregation. Utilizing ...

Toxicity of human ?-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of ...

BackgroundParkinson's disease (PD) is the most common movement disorder. While neuronal deposition of ?-synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, ?-synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of ?-synuclein, however, is unclear.ResultsHere we show that PD-related ...

Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, and the KDEL (Lys-Asp-Glu-Leu motif) receptor (KDELR) plays a key role in ER quality control and in the ER stress response. The subcellular distribution of KDELR is dynamic and related to its ligand binding status and its expression level. Here, we show that KDELR mRNA is upregulated upon thapsigargin treatment, which ...

BackgroundThe mechanisms through which aberrant ?-synuclein (ASYN) leads to neuronal death in Parkinson's disease (PD) are uncertain. In isolated liver lysosomes, mutant ASYNs impair Chaperone Mediated Autophagy (CMA), a targeted lysosomal degradation pathway; however, whether this occurs in a cellular context, and whether it mediates ASYN toxicity, is unknown. We have ...

The interactions between certain ?-synuclein (SNCA) conformations and dopamine (DA) metabolism cause selective DA neuron degeneration in Parkinson's disease (PD). Preclinical research on PD took advantage of increasing studies involving different animal models which express different forms of mutated SNCA. Transgenic animals expressing mutant ?-synucleins ...

BackgroundAlpha-synuclein is a presynaptic protein with a proposed role in neurotransmission and dopamine homeostasis. Abnormal accumulation of ?-synuclein aggregates in dopaminergic neurons of the substantia nigra is diagnostic of sporadic Parkinson's disease, and mutations in the protein are linked to early onset forms of the disease. The folded conformation of the protein ...

Although the structures of the wild type (WT) and mutants (A53T, A30P, E46K) of ?-synuclein (?-syn) proteins related to Parkinson's disease have been studied extensively using both experimental and theoretical tools, the relationships between the structural properties and thermodynamic preferences at a molecular ...

Previously, several studies have demonstrated changes in the levels of small heat shock proteins (sHSP) in the transgenic mouse models of familial amyotrophic lateral sclerosis (fALS) linked to mutations in Cu/Zn superoxide dismutase. Here, we compared the expression of sHSPs in transgenic mouse models of fALS, Parkinson�s disease (PD), dentato-rubral pallido-luysian atrophy (DRPLA) and ...

Aggregation of alpha-synuclein (alpha-SYN) plays a key role in Parkinson's disease. We have previously shown that aggregation of alpha-SYN in vitro is accelerated by addition of FK506 binding proteins (FKBP) and that this effect can be counteracted by FK506, a specific inhibitor of these enzymes. In this paper, we investigated in detail the effect of FKBP12 on early aggregation and on fibril ...

Alpha Synuclein (?-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). ?-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether ?-Syn expression affects ...

The intracellular oligomerization of ?-synuclein is associated with Parkinson's disease and appears to be an important target for disease-modifying treatment. Yet, to date, there is no specific inhibitor for this aggregation process. Using unbiased systematic peptide array analysis, we indentified molecular interaction domains within the ?-synuclein polypeptide that specifically binds ?-synuclein. ...

There is strong evidence for the involvement of alpha-synuclein in the pathologies of several neurodegenerative disorders, including PD (Parkinson's disease). Development of disease appears to be linked to processes that increase the rate at which alpha-synuclein forms aggregates. These processes include increased protein concentration (via either increased rate of synthesis ...

BackgroundMechanisms whereby gene�environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson�s disease (PD)�the second most common neurodegenerative disease�remain elusive.ObjectiveWe created a two-hit [neuroinflammation and mutant ?-synuclein (?-syn) overexpression] animal model to investigate mechanisms through which ...

Because oligomers and aggregates of the protein ?-synuclein (?S) are implicated in the initiation and progression of Parkinson�s disease, investigation of various ?S aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, ?-sheet-rich fibrillar species by incubation of ?S in the presence of ...

Parkinson disease (PD), a prevalent neurodegenerative motor disorder, is characterized by the rather selective loss of dopaminergic neurons and the presence of ?-synuclein-enriched Lewy body inclusions in the substantia nigra of the midbrain. Although the etiology of PD remains incompletely understood, emerging evidence suggests that dysregulated iron homeostasis may be involved. Notably, nigral ...

Genetic alterations in ?-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an ?-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in ?-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein ...

Sequence data are presented for the Saccharomyces cerevisiae TAP1 gene and for a mutant allele, tap1-1, that activates transcription of the promoter-defective yeast SUP4 tRNA(Tyr) allele SUP4A53T61. The degree of in vivo activation of this allele by tap1-1 is strongly affected by the nature of the flanking DNA ...

Parkinson disease is caused by the death of midbrain dopamine neurons from oxidative stress, abnormal protein aggregation, and genetic predisposition. In 2003, Bonifati et al. (23) found that a single amino acid mutation in the DJ-1 protein was associated with early-onset, autosomal recessive Parkinson disease (PARK7). The mutation L166P prevents dimerization that is essential for the antioxidant ...

The fibrillization of ?-synuclein (?-syn) is a key event in the pathogenesis of ?-synucleinopathies. Mutant ?-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides ?-syn, Lewy bodies also contain several ...

Lewy bodies composed of aggregates of ?-synuclein (?S) in the brain are the main histopathological features of Lewy body diseases (LBD) such as Parkinson's disease and dementia with Lewy bodies. Mutations such as E46K, A30P and A53T in the ?S gene cause autosomal dominant LBD in a number of kindreds. Although these mutations accelerate fibril formation, their precise effects at early stages of the ...

?-Synuclein (SYN) is the major component of Lewy bodies, the neuropathological hallmarks of Parkinson's disease (PD). Missense mutations and multiplications of the SYN gene cause autosomal dominant inherited PD. Thus, SYN is implicated in the pathogenesis of PD. However, the mechanism where by SYN promotes neurodegeneration remains unclear. Familial PD with SYN gene mutations are rare because the ...

Overexpression of alpha-synuclein and oxidative stress has been implicated in the neuronal cell death in Parkinson's disease. Alpha-synuclein associates with mitochondria and excessive accumulation of alpha-synuclein causes impairment of mitochondrial functions. However, the mechanism of mitochondrial impairment caused by alpha-synuclein is not fully understood. We recently reported that ...

A consensus about the functions of human wild-type or mutated ?-synuclein (?SYN) is lacking. Both forms of ?SYN are implicated in Parkinson's disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing ...

A consensus about the functions of human wild-type or mutated ?-synuclein (?SYN) is lacking. Both forms of ?SYN are implicated in Parkinson�s disease, whereas the wild-type form is implicated in substance abuse. Interactions with other cellular proteins and organelles may meditate its functions. We developed a series of congenic mouse lines containing ...

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in ...

A subset of familial Parkinson's disease (PD) cases is associated with the presence of disease-causing point mutations in human ?-synuclein [huAS(wt)], including A53T. Surprisingly, the human neurotoxic amino acid 53T is present in non-primate, wild-type sequences of ?-synucleins, including that expressed by mice [mAS(wt)]. Because ...

Individuals with familial Parkinson�s disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T ?-synuclein heterozygotes from Family H, a multigenerational ...

BackgroundMissense mutations and multiplications of the ?-synuclein gene cause autosomal dominant familial Parkinson's disease (PD). ?-Synuclein protein is also a major component of Lewy bodies, the hallmark pathological inclusions of PD. Therefore, ?-synuclein plays an important role in the pathogenesis of familial and sporadic PD. To model ?-synuclein-linked disease in vivo, transgenic mouse ...

... discovered that all mutant forms of p53 tested are capable of binding specifically to p53 response elements present in p53 target genes at lower but ...

... discovered that all mutant forms of p53 tested are capable of binding specifically to p53 response elements present in p53 target genes at lower but ...

The influence of dextran sulfate on the capacity of the herpes simplex virus to form plaques and the possibility of obtaining mutants which are resistant to this inhibitor was studied. Five mutants were isolated which were resistant to dextran sulfate. Th...

The t1 (Toothless) mutation in the rat is an acute form of osteopetrosis. The gene is not an allele of either ia or op that causes, respectively, a transitory and acute form of the disease. Unlike op/op mutants, t1/t1 mutants failed to respond to either p...

The isolation and characterization of mutants that block perithecial development in Neurospora crassa are described. Several classes of mutants have been isolated after uv mutagenesis, and those that block perithecial development when used as the female (protoperithecial) component of a cross have been further characterized. These ...

... However, limited number of available antiandrogens, especially those against mutant forms of androgen receptor found in metastatic prostate ...

The Arabidopsis acd11 mutant exhibits runaway, programmed cell death due to the loss of a putative sphingosine transfer protein (ACD11) with homology to mammalian GLTP. We demonstrate that transgenic expression in Arabidopsis thaliana of human GLTP partially suppressed the phenotype of the acd11 null mutant, resulting in delayed programmed cell death ...

A de novo ?-synuclein A53T (p.Ala53Thr; c.209G>A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cognitive decline. Longitudinal clinical ...

The pathological hallmarks of Parkinson's disease (PD) are degeneration of dopamine (DA) neurons of the substantia nigra (SN) and the presence of alpha-synuclein (?-syn)-rich Lewy bodies in DA cells that remain. To model these aspects of the disease, we previously showed that high titer (5.1�10exp12 gp/ml) AAV1/2 driven expression of A53T ?-syn in the SN of rats caused nigrostriatal pathology ...

Parkinson's disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human ...

BackgroundParkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Methodology/Principal FindingsHere, we used two mouse lines ...

Two-point recombination data of 42 tryptophan synthetase mutants of Neurospora crassa were used to construct a genetic map of the td locus. Twenty- two mutants formed protein (CRM) serologically related to tryptophan synthetase; 20 were CRM negative. CRM positive mutants altered in similar functions appear ...