Table 1.

Known functions of phosphoinositide (PIP) species within the brain and roles in neurodegeneration.

PIP species	Known functions in the brain	Roles in neurodegenerative disease	References
PI(3)P	Key regulator of endocytic trafficking, fusion, and autophagy. Regulates GABAergic neurotransmission at inhibitory post-synapses.	Inhibiting PIP-4 kinase (phosphorylates PI(3)P) reduces mHTT and rescues neurodegeneration in HD drosophila. Excess PI3K (generates PI(3)P) activity in AD, reduced activity in PD.	Heras-Sandoval et al. (2014), Al-Ramahi et al. (2017), Papadopoulos et al. (2017) and Raghu et al. (2019)
PI(4)P	Potential roles in myelin formation. Key role in multiple steps of phagocytosis and other uptake systems.	Pathophysiological concentrations of Aβ inhibit PI4K (generates PI(4)P) activity, both in vitro and in vivo. PI4K inhibition reduces brain pathology in Drosophila models of AD. VAPB, a causal gene for ALS, exerts deleterious effects in the brain by altering PI(4)P levels and distribution. Reduced in AD cortex.	Stokes and Hawthorne (1987), Wu et al. (2006), Levin et al. (2017), Zhang X. et al. (2017), Genevini et al. (2019) and Baba et al. (2020)
PI(5)P	Roles in AKT/mTOR signaling, autophagy, and apoptosis. Regulates chromatin function and transcription in the nucleus. Potential regulators of endosomal trafficking.	Inhibiting PIP-4 kinase [phosphorylates PI(5)P] reduces mHTT and rescues neurodegeneration in HD drosophila.	Boal et al. (2015), Bulley et al. (2015), Vicinanza et al. (2015), Al-Ramahi et al. (2017) and Jacobsen et al. (2019)
PI(3,4)P2	Involved in the maturation of late-stage clathrin-coated pits and fast endophilin-mediated endocytosis. Roles in actin-mediated neurite initiation and dendrite morphogenesis.	Mutations in the PI(3,4)P2 synthesis enzyme INPP5D increase genetic AD risk. Excess PI3K [generates PI(3,4)P2] activity in AD, reduced activity in PD.	Lambert et al. (2013), Heras-Sandoval et al. (2014), Hawkins and Stephens (2016), Jing et al. (2016), Zhang S.-X. et al. (2017) and Casamento and Boucrot (2020)
PI(4,5)P2	Electrical signaling at the plasma membrane (including neurons). Roles in the recycling of synaptic vesicles and synaptic plasticity. Many neurotransmitters utilize the G-protein coupled PLC mediated hydrolysis of PI(4,5)P2 as a key step in signal transduction. Regulates ~100 ion channels and transporters. Regulates cytoskeletal function in neurons. Key regulators of TLR and purinergic signaling. Key role in actin remodeling during chemotaxis. Key role in multiple steps of phagocytosis and other uptake systems.	A genetic variant in PLCγ2, which breaks down PI(4,5)P2, protects against AD. Decreased PI(4,5)P2 metabolism via PLCγ2 in PD, increased PI(4,5)P2 in PD substantia nigra. Overexpression of SYNJ1, which hydrolyzes PI(4,5)P2, acts as a risk factor for AD and appears to contribute to plaque pathology and behavioral deficits in mouse models. Mutations in SYNJ1 associated with early-onset PD.	Wallace and Claro (1993), McIntire et al. (2012), Zhu et al. (2013), Drouet and Lesage (2014), Sims et al. (2017), Miranda et al. (2018), Sekar and Taghibiglou (2018), Ben Romdhan et al. (2018), Bernier et al. (2013b), Le et al. (2014), Hille et al. (2015), Dickson and Hille (2019), Raghu et al. (2019), Xie et al. (2019) and Desale and Chinnathambi (2021)
PI(3,5)P2	Regulates membrane trafficking, endocytic vesicle fission/fusion, organelle pH, intracellular ion channel function. Regulates synaptic strength.	The PI(3,5)P2 synthesis enzyme FIG4 acts as a risk factor for ALS.	Chow et al. (2009), Dong et al. (2010) and McCartney et al. (2014)
PI(3,4,5)P3	Regulates neurotransmitter release. Increased PI(3,4,5)P2 recruits protein kinases (e.g., AKT) to the PM. Regulates purinergic signaling. Key role in actin remodeling during chemotaxis. Key role in multiple steps of phagocytosis and other uptake systems	Excess PI3K [generates PI(3,4,5)P3] activity in AD, reduced activity in PD. Decreased in PD substantia nigra. PTEN [degrades PI(3,4,5)P3] increased in PD.	Bernier et al. (2013b), Khuong et al. (2013), Heras-Sandoval et al. (2014), Maekawa et al. (2014), Schlam et al. (2015), Sekar and Taghibiglou (2018), Katan and Cockcroft (2020) and Desale and Chinnathambi (2021)

mHTT, mutant Huntington protein; AD, Alzheimer’s disease; HD, Huntington’s disease; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; Aβ, amyloidβ; VAPB, VAMP associated protein B and C; AKT, Protein kinase B mammalian target of rapamycin; TLR, toll-like receptor; SYNJ1, synaptojanin 1; FIG4, Factor induced gene 4; PLC, phospholipase C.