SPN
Leukosialin precursor (GPL115) (Galactoglycoprotein) (GALGP) (Leukocyte sialoglycoprotein) (Sialophorin) (CD43 antigen) [Contains: CD43 cytoplasmic tail (CD43-ct) (CD43ct)] [CD43]
Publications[править]
Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2 ) and control (Lrrk2 ) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2 and Lrrk2 mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2 and Lrrk2 mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2 striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2 and R1441C SPNs. Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.
Keywords
- And aging
- Dendritic hypotrophy
- Excitability
- G2019S
- GABAA
- LRRK2
- Nuclear DNA damage
- Nuclear hypertrophy
- Nuclear invagination
- Parkinson’s disease
- R1441C
- Striatal spiny projection neuron
Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls.
MeSH Terms
- Adaptation, Physiological
- Aged, 80 and over
- Female
- Gene Expression
- Genotype
- Humans
- Longevity
- Male
- Polymorphism, Single Nucleotide
Keywords
- Ageing
- Centenarian
- Centenarios
- Envejecimiento
- Extreme longevity
- Longevidad
- Longevidad extrema
- Longevity