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Combined knockout of Lrrk2 and Rab29 does not result in behavioral abnormalities in vivo
bioRxiv - Animal Behavior and Cognition Pub Date : 2020-05-15 , DOI: 10.1101/2020.05.13.093708
Melissa Conti Mazza , Victoria Nguyen , Alexandra Beilina , Jinhui Ding , Mark R. Cookson

Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.

中文翻译:

联合敲除Lrrk2和Rab29不会导致体内行为异常

LRRK2基因的编码突变编码大蛋白激酶,已被证明可导致家族性帕金森氏病(PD)。LRRK2突变的直接生物学后果是增加激酶活性,从而提示该酶的抑制可能在治疗上减缓疾病的进展。全基因组关联研究确定了LRRK2周围的染色体基因座及其拟议的底物之一RAB29,作为导致散发性PD终生风险的原因。考虑到LRRK2和RAB29之间在基因和蛋白质水平上相互作用的证据,在这里我们生成了双敲除小鼠模型,并确定了衰老对脑功能是否有任何影响。通过一系列电机和非电机行为测试,我们仅注意到18-24个月的Rab29 -/-和双倍(Lrrk2 -/- / Rab29 -/-与野生型小鼠相比,基因敲除小鼠在旷野的运动行为减少。但是,在黑质致密部(SNc)多巴胺神经元数量或SNc和纹状体中酪氨酸羟化酶水平上均未见基因型差异,这可能反映了PD样病理。这些结果表明,Lrrk2和Rab29的耗竭至少在小鼠中是可以忍受的,并支持该途径可能能够安全地靶向人类的治疗方法。
更新日期:2020-05-15
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