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Biochemical and morphological consequences of human ?-synuclein expression in a mouse ?-synuclein null background.

ABSTRACT: 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 various allele doses or combinations of the human wild-type ?SYN (hw?SYN) or a doubly mutated (A30P*A53T) ?SYN (hm(2) ?SYN) in a C57Bl/6J line spontaneously deleted in mouse ?SYN (C57BL/6JOla). Both transgenes had a functional role in the nigrostriatal system, demonstrated by significant elevations in striatal catecholamines, metabolites and the enzyme tyrosine hydroxylase compared with null-mice without a transgene. Consequences occurred when the transgenes were expressed at a fraction of the endogenous level. Hemizygous congenic mice did not exhibit any change in the number or size of dopaminergic neurons in the ventral midbrain at 9 months of age. Human ?SYN was predominantly located in neuronal cell bodies, neurites, synapses, and in intraneuronal/intraneuritic aggregates. The hm(2) ?SYN transgene resulted in more aggregates and dystrophic neurites than did the hw5 transgene. The hw?SYN transgene resulted in higher expression of two striatal proteins, synaptogamin 7 and UCHL1, compared with the levels of the hm(2) ?SYN transgene. These observations suggest that mutations in ?SYN may impair specific functional domains, leaving others intact. These lines may be useful for exploring interactions between h?SYN and environmental or genetic risk factors in dopamine-related disorders using a mouse model.

SUBMITTER: Prasad K

PROVIDER: S-EPMC3072281 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Biochemical and morphological consequences of human α-synuclein expression in a mouse α-synuclein null background.

Prasad Kavita K Tarasewicz Elizabeth E Strickland Pamela A Ohman PA O'Neill Michael M Mitchell Stephen N SN Merchant Kalpana K Tep Samnang S Hilton Kathryn K Datwani Akash A Buttini Manuel M Mueller-Steiner Sarah S Richfield Eric K EK

The European journal of neuroscience 20110128 4

A consensus about the functions of human wild-type or mutated α-synuclein (αSYN) is lacking. Both forms of αSYN 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 various allele doses or combinations of the human wild-type αSYN (hwαSYN) or a doubly mutated (A30P*A53T) αSYN (hm(2) αSYN) in a C57Bl/6J line spo ...[more]

PMID: 21272100

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Project description:Abstract Objectives Despite the high frequency of segmentation anomalies in the human sacrum, their evolutionary and clinical implications remain controversial. Specifically, inconsistencies involving the classification and counting methods obscure accurate assessment of lumbosacral transitional vertebrae. Therefore, we aim to establish more reliable morphological and morphometric methods for differentiating between sacralizations and lumbarizations in clinical and paleontological contexts. Materials and Methods Using clinical CT data from 145 individuals aged 14–47 years, vertebral counts and the spatial relationship between the sacrum and adjoining bony structures were assessed, while the morphological variation of the sacrum was assessed using geometric morphometrics based on varied landmark configurations. Results The prevalence of lumbosacral and sacrococcygeal segmentation anomalies was 40%. Lumbarizations and sacralizations were reliably distinguishable based on the spatial relationship between the iliac crest and the upward or downward trajectory of the linea terminalis on the sacrum. Different craniocaudal orientations of the alae relative to the corpus of the first sacral vertebra were also reflected in the geometric morphometric analyses. The fusion of the coccyx (32%) was frequently coupled with lumbarizations, suggesting that the six‐element sacra more often incorporate the coccyx rather than the fifth lumbar vertebra. Conclusions Our approach allowed the consistent identification of segmentation anomalies even in isolated sacra. Additionally, our outcomes either suggest that homeotic border shifts often affect multiple spinal regions in a unidirectional way, or that sacrum length is highly conserved perhaps due to functional constraints. Our results elucidate the potential clinical, biomechanical, and evolutionary significance of lumbosacral transitional vertebrae. Direct morphological comparison of lumbosacral segmentation anomalies, that is, sacralization (blue) and lumbarization (yellow).

Project description:Targeted mutant models are common in mechanistic toxicology experiments investigating the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individuals. Key models include those for xenosensing transcription factors and cytochrome P450s (CYP). Here we investigated changes in transcript levels, protein expression, and steroid hydroxylation of several xenobiotic detoxifying CYPs in constitutive androstane receptor (CAR)-null and two CYP-null mouse models that have subfamily members regulated by CAR; the Cyp3a-null and a newly described Cyp2b9/10/13-null mouse model. Compensatory changes in CYP expression that occur in these models may also occur in polymorphic humans, or may complicate interpretation of ADME studies performed using these models. The loss of CAR causes significant changes in several CYPs probably due to loss of CAR-mediated constitutive regulation of these CYPs. Expression and activity changes include significant repression of Cyp2a and Cyp2b members with corresponding drops in 6α- and 16β-testosterone hydroxylase activity. Further, the ratio of 6α-/15α-hydroxylase activity, a biomarker of sexual dimorphism in the liver, indicates masculinization of female CAR-null mice, suggesting a role for CAR in the regulation of sexually dimorphic liver CYP profiles. The loss of Cyp3a causes fewer changes than CAR. Nevertheless, there are compensatory changes including gender-specific increases in Cyp2a and Cyp2b. Cyp2a and Cyp2b were down-regulated in CAR-null mice, suggesting activation of CAR and potentially PXR following loss of the Cyp3a members. However, the loss of Cyp2b causes few changes in hepatic CYP transcript levels and almost no significant compensatory changes in protein expression or activity with the possible exception of 6α-hydroxylase activity. This lack of a compensatory response in the Cyp2b9/10/13-null mice is probably due to low CYP2B hepatic expression, especially in male mice. Overall, compensatory and regulatory CYP changes followed the order CAR-null > Cyp3a-null > Cyp2b-null mice.

Dataset Information

Biochemical and morphological consequences of human ?-synuclein expression in a mouse ?-synuclein null background.

Publications

Biochemical and morphological consequences of human α-synuclein expression in a mouse α-synuclein null background.

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