From:  Should we rethink neurodegeneration?

 Genetic and environmental background of HD, AD, PD, and ALS

HDADPDALS
Genetic backgroundMonogenic autosomal dominant inheritance

  • Unstable CAG repeat expansion in HTT


Genetic modifiers: CAA interruptions of the CAG repeat, genes associated with pathways involved in DNA repair, mitochondrial fission, and oxidoreductase activity		Monogenic forms with autosomal dominant inheritance: PSEN1, PSEN2, APP GWAS highlights genes expressed in immune tissuesMonogenic forms

  • Autosomal dominant inheritance: SNCA, LRRK2, VPS35

  • Autosomal recessive inheritance: PRKN, PINK1, DJ1, RFC1

  • X-linked: XDP


GWAS highlights substantia nigra-related genes		Monogenic forms

  • Autosomal dominant inheritance: C9orf72, SOD1, TDP-43, FUS, OPTN

  • Autosomal recessive inheritance: SOD1, FUS, Alsin, VAPB, OPTN

  • X-linked inheritance: UBQLN2


GWAS highlights genes associated with glutamate-mediated neurotransmission and excitability, regulation of neuronal excitability, autophagy, cytoskeletal organization, and axonal transport
Smoking++–+
Diabetes?++–
Hypertension+++ (?)+ (systolic)
– (diastolic)
Statins–– (?)–0
Coffee+– (?)–0
TBI?+++
NSAIDs?–00
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Selected characteristics are presented and compared with no intent to perform an exhaustive review. “+” denotes increased risk of disease or its severity while “–” denotes a decreased risk. No association is marked by “0” and uncertainty with “?”. GWAS: genome-wide association study; NSAIDs: non-steroidal anti-inflammatory drugs; TBI: traumatic brain injury; CAG: cytosine-adenine-guanine; CAA: cytosine-adenine-adenine; PSEN1: presenilin 1; APP: amyloid precursor protein; LRRK2: leucine-rich repeat kinase 2; VPS35: vacuolar protein sorting 35; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN-induced kinase 1; DJ1: PD protein 7; XDP: X-linked dystonia-parkinsonism; FUS: fused in sarcoma; OPTN: optineurin; VAPB: vesicle-associated membrane protein-associated protein B/C; UBQLN2: ubiquilin 2