パーキンソン病（Parkinson’s disease）と発病の仮説、パーキンの働きなどについて

Brain-first・body-first仮説とは？

パーキンソン病は、体のどの部分から始まるのか？に関して、脳から始まる病型と体（特に腸）から始まる病型の２つに分かれるという仮説があるそうです。

  • 腸管に端を発した病理が迷走神経を介して脳に到達するという「PDの腸管起源説」が注目を集めている。
  • 上部消化管の粘膜損傷の既往は臨床的PD診断リスクの上昇と関連していることをJAMA Netw Open（2024; 7: e2431949）
  • 粘膜損傷と臨床的PDリスクとの有意な関連：調整後HR 1.76、95%CI 1.11～2.51、P＝0.01

パーキンソン病の腸管起源説に新知見 上部消化管の粘膜損傷が発端か 2024年9月18日 16:26　MedicalTribune

Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. https://academic.oup.com/brain/article/143/10/3077/5896254

The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction.　https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd223511

Brain-first and body-first Parkinson’s disease: are there subgroups of prodromal patients? VJNeurology チャンネル登録者数 4480人

  1. EAN 2021 | Brain-first and body-first Parkinson’s disease: are there subgroups of prodromal patients? Filip Scheperjans • 1 Jun 2021

How valid is the brain-first vs body-first model of Parkinson’s disease? VJNeurology チャンネル登録者数 4480人　Alberto Espay, MD, FAAN, University of Cincinnati, Cincinnati, OH

Brain-first and body-first仮説に関するレビュー論文

  1. Neurobiology of Disease Clinical and imaging evidence of brain-first and body-first Parkinson’s disease　Neurobiology of Disease Volume 164, March 2022, 105626　Braak‘s hypothesis has been extremely influential over the last two decades. 　By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes.
  2. Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis　J Parkinsons Dis . 2019;9(s2):S281-S295. doi: 10.3233/JPD-191721.

Brain-first and body-first仮説に関する原著論文

  1. Body-First Subtype of Parkinson’s Disease with Probable REM-Sleep Behavior Disorder Is Associated with Non-Motor Dominant Phenotype　J Parkinsons Dis . 2022;12(8):2561-2573. doi: 10.3233/JPD-223511.
  2. Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study Brain, Volume 143, Issue 10, October 2020, Pages 3077–3088, https://doi.org/10.1093/brain/awaa238 Published: 24 August 2020

黒質（中脳）と青斑核（橋）と迷走神経背側核との位置関係

黒質は運動を司る領域で、黒質のドーパミン作動性ニューロンが変性すると運動障害が生じます。青斑核はREM睡眠に関連していて、青斑核が変性するとREM睡眠の異常が見られます。迷走神経背側核からは、副交感神経が伸びて内蔵を支配しています。

  1. 細胞間の伝搬経路 (点線)や、青斑核から上行する経路の実態はヒト脳では明らかになっておらず、病変が上行するという仮説の構造背景はヒト脳では未確定である(点線矢印)。　https://www.igakuken.or.jp/topics/2015/1007.html　わかりやすい図

Braak’s Hypothesis

Braak’s Hypothesis: This theory suggests that Parkinson’s disease may start in the peripheral nervous system or the gut and then progress to the brain. According to this hypothesis, abnormal alpha-synuclein protein aggregates may initiate the disease process in the enteric nervous system and later spread to the brain through the vagus nerve.　https://chat.openai.com/

It has been hypothesized that α-synuclein inclusions initially form in nerve terminals of the enteric nervous system, and then subsequently spread via autonomic connections to the dorsal motor nucleus of the vagus and intermediolateral cell columns of the sympathetic system (Braak et al., 2003a, b; Borghammer, 2018).

(引用元：Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study Brain, Volume 143, Issue 10, October 2020, Pages 3077–3088, https://doi.org/10.1093/brain/awaa238）PDF

  1. The dorsal motor nucleus of vagus (図）
  2. The intermediolateral nucleus (IML) is a region of grey matter found in one of the three grey columns of the spinal cord, the lateral grey column. The intermediolateral cell column exists at vertebral levels T1 – L3. It mediates the entire sympathetic innervation of the body, but the nucleus resides in the grey matter of the spinal cord.

デュアルヒット仮説とは

the idea that PD pathology may in fact originate in synapses of the peripheral nervous system (PNS) and invade the brain from the olfactory epithelium and via retrograde axonal transport through the vagus, termed the dual-hit hypothesis [4].　https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd191721

The progressive, neurodegenerative process underlying idiopathic Parkinson’s disease is associated with the formation of proteinaceous inclusion bodies that involve a few susceptible neuronal types of the human nervous system. In the lower brain stem, the process begins in the dorsal motor nucleus of the vagus nerve and advances from there essentially upwards through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain until it reaches the cerebral cortex. With time, multiple components of the autonomic, limbic, and motor systems become severely impaired. All of the vulnerable subcortical grays and cortical areas are closely interconnected. Incidental cases of idiopathic Parkinson’s disease may show involvement of both the enteric nervous system and the dorsal motor nucleus of the vagus nerve. This observation, combined with the working hypothesis that the stereotypic topographic expansion pattern of the lesions may resemble that of a falling row of dominos, prompts the question whether the disorder might originate outside of the central nervous system, caused by a yet unidentified pathogen that is capable of passing the mucosal barrier of the gastrointestinal tract and, via postganglionic enteric neurons, entering the central nervous system along unmyelinated praeganglionic fibers generated from the visceromotor projection cells of the vagus nerve.

J Neural Transm (Vienna) . 2003 May;110(5):517-36. doi: 10.1007/s00702-002-0808-2. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen H Braak 1, U Rüb, W P Gai, K Del Tredici Affiliations expand PMID: 12721813 DOI: 10.1007/s00702-002-0808-2

レビー小体とは

Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases.　https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01288-2

Metaiodobenzylguanidine (MIBG) とは

Metaiodobenzylguanidine (MIBG) was first developed in USA, in Michigan University Medical Centre, in early 1970, for imaging the adrenal medulla and its disease.1 MIBG, a guanithidine analog, is taken up by an active mechanism into the neuroendocrine cells due to its similarities with nor-epinephrine. It came into clinical practice in 1981 for localization of pheochromocytoma (pheo).2 In course of time, MIBG demonstrated its ability to concentrate in tumors of the neural crest origin such as neuroblastoma (NBL),3 carcinoids and medullary carcinoma of the thyroid.4, 5 Due to good selective uptake and retention of MIBG by these tumors, its potential was explored for therapy of neuroendocrine tumors (NETs) as well. MIBG is labeled with 123-Iodine (123I) which is exclusively used for imaging and also with 131-Iodine (131I); which can be used both for imaging and therapy of NBL or other MIBG avid neural crest tumors.　https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475939/

パーキンソン病とパーキン遺伝子

パーキンソン病の原因遺伝子としてパーキンが見つかっています。パーキンはE3ユビキチンリガーゼの一種です。

以下はconsensus.appによる回答：

パーキンソン病におけるパーキンの役割

パーキンソン病（PD）は、神経変性疾患であり、特にドーパミン作動性ニューロンの喪失が特徴です。パーキン（Parkin）は、E3ユビキチンリガーゼとして知られ、ミトコンドリアの品質管理やタンパク質の分解に関与しています。パーキンの機能不全がPDの発症にどのように影響するかについて、多くの研究が行われています。

  • パーキンの機能喪失とPDの関連性
    • パーキンのE3リガーゼ活性の喪失が、遺伝性および散発性のPDの病因に寄与する。
    • パーキンの機能不全は、特定の基質の有害な蓄積を引き起こし、ドーパミン作動性ニューロンの生存に重要な役割を果たす。
  • パーキンの神経保護作用
    • パーキンの過剰発現は、α-シヌクレイン誘発性の神経病理を軽減し、ドーパミン作動性ニューロンの保護に寄与する。
    • パーキンは、6-OHDAラットモデルにおいて神経毒性に対する強力な神経保護作用を示し、行動の改善も観察された。
  • パーキンの多機能性と調節
    • パーキンは、ミトコンドリアの恒常性やストレス関連のシグナル伝達など、さまざまな細胞機能に関与し、これらの機能が神経保護に寄与する。
    • パーキンの活性は、酸化ストレスやニトロソ化ストレスによって調節され、これがPDの病因に関連する可能性がある。
  • パーキンとLewy小体の形成
    • パーキンは、Lewy小体の形成に関与し、α-シヌクレインと共局在することが示されている。

パーキンの活性は、パーキンソン病の発症と進行において重要な役割を果たします。パーキンのE3リガーゼ活性の喪失は、遺伝性および散発性のPDの病因に寄与し、ドーパミン作動性ニューロンの生存に不可欠です。また、パーキンの過剰発現やその多機能性は、神経保護作用を持ち、PDの治療における潜在的なターゲットとなり得ます。