Table 1 Other protein aggregates associated with sleep disturbances

α-synuclein (PD, DLB)

 α-synuclein (α-syn) present in locus coeruleus and raphe nucleus; PD-related sleep disruptions reviewed in [125]

 REM sleep behavior disorder (RBD)—physical and often violent dream-enactment, common co-morbidity, and early sign of PD and DLB

 43% of RBD patients develop PD, an additional 25% DLB [126], with presence of α-syn aggregates in RBD patients [127]; > 90% of RBD patients exhibit any neurodegenerative disease after 14 years, additionally including MCI and AD [126]

• ↑ α-syn levels with impairment in UPR, UPS and ALP [1, 125], and spread by neuronal connectivity [128]

• Exact linkage of α-syn to glymphatic clearance requires further validation; however, SWS enhancement with ↑ AQP4 channels and ↓ pathology, SWS impairment linked to ↑ α-syn pathology in PD mouse models [129]

• AQP4 (+/-) mice with α-syn intrastriatal injections exhibit advanced cortical and striatal α-syn deposition and higher insoluble levels [130]; ligating deep cervical lymph nodes ↓ clearance and ↑ α-syn deposition in A53T mice [131]

SWS – reduced AQP4, potentially less α-synuclein clearance by glymphatics

REM – potentially increased oxidative species with REM loss [125, 132, 133]; potential exacerbation of DLB-related cognitive impairments [68, 69]

Circadian rhythm – UPR, UPS, ALP impaired, leading to failed degradation of α-synuclein

Synucleinopathy-related RBD is commonly treated with melatonin or Clonazepam (a benzodiazepine) [134]. Other sleep therapies may have success in synucleinopathies, such as orexin antagonists: one clinical trial pilot study for safety and efficacy of Suvorexant for insomnia in PD (ClinicalTrials.gov Identifier: NCT02729714, see Table 2)

Continued study in role of glymphatic clearance of α-syn, given the relationship between AQP4 polymorphisms and cognition in PD [42] and increased α-syn from sleep disturbances [125]

Future preclinical studies may focus on cellular proteostasis of α-syn in relation to sleep disturbances and in sleep-controlling neurons

TDP-43 (ALS, FTD)

 TDP-43 inclusions are present in hypothalamus of ALS patients, likely at stage III and IV when TDP-43 is widespread; > 1/3 loss of orexinergic neurons [111, 112, 124]

 Potential for role of orexin and hypothalamus pathology in behavioral variant FTD [123]

 ALS patients have disturbed sleep, most commonly from sleep-disordered breathing, including obstructive sleep apnea and hypoventilation. Insomnia, RBD and other sleep impairments can occur as well, reviewed in [122]

• Small, soluble TDP-43 species are degraded by UPS; insoluble TDP-43 aggregates are broken down by ALP, and can require UPS for full clearance [135]. Impaired glymphatic clearance of MRI tracer in TDP-43 mouse model [136]

• ER stress and UPR pathways are involved in ALS, including with the presence of TDP-43, FUS and/or SOD1 [137]

SWS – loss in SWS can exacerbate glymphatic deficits seen early in a TDP-43 mouse model [136]; further characterization of the role of glymphatics with TDP-43 and ALS is necessary

Circadian rhythm – disrupted equilibrium of TDP-43 soluble and insoluble species from UPS and ALP impairment

Further research is needed into the role (if any) that TDP-43 inclusions play in sleep disturbances, potentially through impairment of hypothalamic neurons, or neuromodulatory systems related to sleep (i.e., noradrenaline, serotonin)

Cases of FTD-related TDP-43 proteinopathy have rare LC inclusions, whereas FTD-related tau proteinopathy is prominent in LC [138]

Hypothalamic impairments in ALS may be more related to metabolic changes, as seen by neuronal loss in the melanocortin pathway in SOD1, TDP-43 and FUS mouse models; upstream serotonin loss observed in the SOD1 mutant mice [139]

In sum, evidence indicates hypothalamic metabolic effects are more prominent than hypothalamic sleep deficits from TDP-43, yet there is a potential role of C9orf72 dipeptide repeat inclusions in sleep-controlling neurons exacerbating sleep impairments in ALS (see Sect. "Neurodegenerative disease biomarkers and their relationship to sleep"; [110])

FUS (ALS, FTD)

 FUS knock-in rat model exhibits increased wakefulness, decreased REM sleep in early dark phase coinciding with upregulation of orexin receptor type 2 [140]

• FUS regulates transcription of genes involved in autophagy activation and autophagosome formation (shown in vitro), indicating a role in autophagic flux [141]

• Impaired with FUS loss-of-function in vitro [141]

• Aggregated FUS is mis-localized from nucleus to cytoplasm, and is cleared by ALP and UPS, with evidence suggesting cytoplasmic clearance by the former [142], and nuclear clearance (not exclusively) by the latter pathway [143], reviewed in [144]

Circadian rhythm and REM – arrhythmicity in REM sleep and ↑ orexinergic-mediated wakefulness can impact balance of UPS and ALP via impaired clock gene control and sleep loss (see Sect. "Sleep loss dysregulates protein degradation"), leading to ↓ clearance of toxic FUS in nucleus and cytoplasm

Future work can utilize preclinical mouse models to further investigate the regulation of autophagy by FUS. This may elucidate if ALP dysregulation from FUS loss of function in ALS or FTD (when mis-localized to cytoplasm) contributes to proteinopathy, and if this impacts sleep-controlling neurons and has any bearing upon sleep disturbances

Further discussion above in TDP-43 section

Htt (HD)

 Increased dark-cycle sleep (REM and NREM) but decreased theta and delta power in a HD mouse model starting at the pre-symptomatic stage, indicating likely impaired sleep quality and inability to sustain wakefulness [145]. Circadian arrhythmicity and disrupted clock gene expression in a HD drosophila model [146]

 HD patients exhibit hypothalamic grey matter reductions and impaired sleep (low efficiency, high arousals, less total sleep time, impaired REM and NREM, etc.) [147, 148]

• Htt is cleared by autophagy and aggregates impair ALP function. UPS is impaired in HD animal models. Reviewed in [1]

• Htt is cleared by glymphatics [149]

• ER stress and UPR play a role in HD, mediating Htt toxicity, reviewed in [150]

As described previously for Aβ, α-syn and tau, impaired SWS, REM, and circadian rhythmicity impacts glymphatics, ALP, UPR and UPS, potentially impairing Htt degradation and clearance

Two active, recruiting clinical trials with sleep modifying therapies for HD:

1. Melatonin efficacy for sleep disturbances in HD (ClinicalTrials.gov Identifier: NCT04421339)

2. SWS enhancement with an acoustic stimulation sleep headband device in HD, PD and MCI (ClinicalTrials.gov Identifier: NCT04589182). Successful promotion of SWS may facilitate Htt clearance via glymphatics [149]

Given the impact of ER stress and UPR in HD [150], future preclinical work may investigate potential UPR-sleep interactions in HD models