Bidirectional Relationship Between Sleep Disturbances and Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Both diseases share common clinical and pathological features: the gradual progression of neurological and psychiatric symptoms caused by neuronal dysfunction and neuronal cell death due to the accumulation of misfolded and neurotoxic proteins. Furthermore, both of them are multifactorial diseases in which both genetic and non-genetic factors contribute to the disease course. Non-genetic factors are of particular interest for the development of preventive and therapeutic approaches for these diseases because they are modifiable; of these, sleep is a particularly intriguing factor. Sleep disturbances are highly prevalent among both patients with AD and PD. To date, research has suggested that sleep disturbances are a consequence as well as a risk factor for the onset and progression of AD, which implies a bidirectional relationship between sleep and AD. Whether such a relationship exists in PD is less certain, albeit highly plausible given the shared pathomechanisms. This review examines the current evidence for the bidirectional relationship between sleep and PD. It includes research in both humans and animal models, followed by a discussion of the current understanding of the mechanisms underlying this relationship. Finally, potential avenues of research toward achieving disease modification to treat or prevent PD are proposed. Although further efforts are crucial for preventing the onset and slowing the progress of PD, it is evident that sleep is a valuable candidate target for future interventions to improve the outcomes of PD patients

Minimal dilatations of pseudo-Anosovs generated by the magic 3-manifold and their asymptotic behavior

This paper concerns the set $\hat{\mathcal{M}}$ of pseudo-Anosovs which occur as monodromies of fibrations on manifolds obtained from the magic 3-manifold $N$ by Dehn filling three cusps with a mild restriction. We prove that for each $g$ (resp. $g \not\equiv 0 \pmod{6}$), the minimum among dilatations of elements (resp. elements with orientable invariant foliations) of $\hat{\mathcal{M}}$ defined on a closed surface $\varSigma_g$ of genus $g$ is achieved by the monodromy of some $\varSigma_g$-bundle over the circle obtained from $N(\tfrac{3}{-2})$ or $N(\tfrac{1}{-2})$ by Dehn filling two cusps. These minimizers are the same ones identified by Hironaka, Aaber-Dunfiled, Kin-Takasawa independently. In the case $g \equiv 6 \pmod{12}$ we find a new family of pseudo-Anosovs defined on $\varSigma_g$ with orientable invariant foliations obtained from N(-6) or N(4) by Dehn filling two cusps. We prove that if $\delta_g^+$ is the minimal dilatation of pseudo-Anosovs with orientable invariant foliations defined on $\varSigma_g$, then $$\limsup_{\substack{g \equiv 6 \pmod{12} g \to \infty}} g \log \delta^+_g \le 2 \log \delta(D_5) \approx 1.0870,$$ where $\delta(D_n)$ is the minimal dilatation of pseudo-Anosovs on an $n$-punctured disk. We also study monodromies of fibrations on N(1). We prove that if $\delta_{1,n}$ is the minimal dilatation of pseudo-Anosovs on a genus 1 surface with $n$ punctures, then $$\limsup_{n \to \infty} n \log \delta_{1,n} \le 2 \log \delta(D_4) \approx 1.6628.$$Comment: 46 pages, 14 figures; version 3: Major change in Section 2.1, and minor correction

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.ArticleeNeuro.4(2):e0250(2017)journal articl

家族性パーキンソン病の責任遺伝子DJ-1を欠損させたニワトリ由来DT40細胞はミトコンドリア機能不全を呈する

京都大学0048新制・課程博士博士(医学)甲第18144号医博第3864号新制||医||1002(附属図書館)31002京都大学大学院医学研究科医学専攻(主査)教授 松原 和夫, 教授 髙橋 淳, 教授 福山 秀直学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDGA

Sleep Disturbance as a Potential Modifiable Risk Factor for Alzheimer’s Disease

Sleep disturbance is a common symptom in patients with various neurodegenerative diseases, including Alzheimer’s disease (AD), and it can manifest in the early stages of the disease. Impaired sleep in patients with AD has been attributed to AD pathology that affects brain regions regulating the sleep⁻wake or circadian rhythm. However, recent epidemiological and experimental studies have demonstrated an association between impaired sleep and an increased risk of AD. These studies have led to the idea of a bidirectional relationship between AD and impaired sleep; in addition to the conventional concept that impaired sleep is a consequence of AD pathology, various evidence strongly suggests that impaired sleep is a risk factor for the initiation and progression of AD. Despite this recent progress, much remains to be elucidated in order to establish the benefit of therapeutic interventions against impaired sleep to prevent or alleviate the disease course of AD. In this review, we provide an overview of previous studies that have linked AD and sleep. We then highlight the studies that have tested the causal relationship between impaired sleep and AD and will discuss the molecular and cellular mechanisms underlying this link. We also propose future works that will aid the development of a novel disease-modifying therapy and prevention of AD via targeting impaired sleep through non-pharmacological and pharmacological interventions

O2‐06‐05: Toward understanding pathogenesis of ubqln2‐mediated ftd/als

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152677/1/alzjjalz201507163.pd

P1–096: The role of Fbxo2 in APP turnover and processing

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152907/1/alzjjalz201305317.pd