Lazarillo-related Lipocalins confer long-term protection against type I Spinocerebellar Ataxia degeneration contributing to optimize selective autophagy

Abstract

BackgroundA diverse set of neurodegenerative disorders are caused by abnormal extensions of polyglutamine (poly-Q) stretches in various, functionally unrelated proteins. A common feature of these diseases is altered proteostasis. Autophagy induction is part of the endogenous response to poly-Q protein expression. However, if autophagy is not resolved properly, clearance of toxic proteins or aggregates cannot occur effectively. Likewise, excessive autophagy induction can cause autophagic stress and neurodegeneration. The Lipocalins ApoD, Glial Lazarillo (GLaz) and Neural Lazarillo (NLaz) are neuroprotectors upon oxidative stress or aging. In this work we test whether these Lipocalins also protect against poly-Q-triggered deterioration of protein quality control systems.ResultsUsing a Drosophila retinal degeneration model of Type-1 Spinocerebellar Ataxia (SCA1) combined with genetic manipulation of NLaz and GLaz expression, we demonstrate that both Lipocalins protect against SCA1 neurodegeneration. They are part of the endogenous transcriptional response to SCA1, and their effect is non-additive, suggesting participation in a similar mechanism. GLaz beneficial effects persist throughout aging, and appears when expressed by degenerating neurons or by retinal support and glial cells. GLaz gain-of-function reduces cell death and the extent of ubiquitinated proteins accumulation, and decreases the expression of Atg8a/LC3, p62 mRNA and protein levels, and GstS1 induction. Over-expression of GLaz is able to reduce p62 and ubiquitinated proteins levels when rapamycin-dependent and SCA1-dependent inductions of autophagy are combined. In the absence of neurodegeneration, GLaz loss-of-function increases Atg8a/LC3 mRNA and p62 protein levels without altering p62 mRNA levels. Knocking-down autophagy, by interfering with Atg8a or p62 expression or by expressing dominant-negative Atg1/ULK1 or Atg4a transgenes, rescues SCA1-dependent neurodegeneration in a similar extent to the protective effect of GLaz. Further GLaz-dependent improvement is concealed.ConclusionsThis work shows for the first time that a Lipocalin rescues neurons from pathogenic SCA1 degeneration by optimizing clearance of aggregation-prone proteins. GLaz modulates key autophagy genes and lipid-peroxide clearance responsive genes. Down-regulation of selective autophagy causes similar and non-additive rescuing effects. These data suggest that SCA1 neurodegeneration concurs with autophagic stress, and places Lazarillo-related Lipocalins as valuable players in the endogenous protection against the two major contributors to aging and neurodegeneration: ROS-dependent damage and proteostasis deterioration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0009-8) contains supplementary material, which is available to authorized users.

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

“…In this context, we first find that mouse lifespan is not altered by ApoD deletion, in spite of the known metabolic (Do Carmo et al, 2009;Jimenez-Palomares et al, 2011;Perdomo et al, 2010) and cardiovascular (Leung et al, 2004;Tsukamoto et al, 2013) ApoD-dependent alterations, as well as the longevity regulatory functions described for invertebrate ApoD homologues (Hull-Thompson et al, 2009;Ruiz et al, 2011;Sanchez et al, 2006). However, within this normal lifespan, ApoD-KO mice clearly show signs of neurodegeneration, cognitive impairment and behavioral alterations at an age when mortality risks are still low.…”

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

“…However, in these pathologies, autophagy fails to remove toxic molecules due to their abundance and to the inhibitory effects of long polyQ mutation on mechanism initiating autophagy [167]. Consistently, pharmacological treatments targeting autophagy provided beneficial effects in several models of hereditary cerebellar ataxia [168][169][170][171]. Moreover, positive outcomes associated with changes in autophagy were also induced by motor training administered at presymptomatic stages in the tambaleante (tbl) mouse model of ataxia [172].…”

Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

“…In addition to huntingtin, expansion of polyQ-encoding CAG repeats in several genes have also been found in other polyQ repeat diseases, such as Ataxin-1 in spinocerebellar ataxia type 1 (SCA1), Ataxin-2 in SCA2, Atantin-3 in SCA3, α1 A -voltage-dependent calcium channel (CACNA1A) in SCA6, Ataxin-7 in SCA7, Atrophin-1 in dentatorubral-pallidoluysian atrophy (DRPLA), and androgen receptor in SBMA (Zoghbi and Orr, 2000; Del Cano-Espinel et al, 2015). All polyQ repeat disorders are dominant neurodegenerative diseases and are associated with pathological intracellular inclusion bodies in the affected brain regions (Ross et al, 1997; Zoghbi and Orr, 2000).…”