Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.

We used primary cultures of cortical neurons to examine the relationship between ␤-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to ␤-amyloid peptide (␤AP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3␤. DKK1 was induced at late times after ␤AP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in ␤AP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by ␤-amyloid and is critically involved in the process of tau phosphorylation.

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The Wilms tumor suppressor gene WTI is implicated in the ontogeny of genito-urinary abnormalities, including Denys-Drash syndrome and Wilms tumor of the kidney. WTI encodes Kruppel-type zinc finger proteins that can regulate the expression of several growth-related genes, apparently by binding to specific DNA sites located within 5' untranslated leader regions as well as 5' promoter sequences.Both WT1 and a closely related early growth response factor, EGR1, can bind the same DNA sequences from the mouse gene encoding insulin-like growth factor 2 (Igf-2). We report that WT1, but not EGR1, can bind specific Igf-2 exonic RNA sequences, and that the zinc fingers are required for this interaction. WT1 zinc finger 1, which is not represented in EGR1, plays a more significant role in RNA binding than zinc finger 4, which does have a counterpart in EGRI. Furthermore, the normal subnuclear localization of WT1 proteins is shown to be RNase, but not DNase, sensitive. Therefore, WT1 might, like the Kruppel-type zinc finger protein TFIIIA, regulate gene expression by both transcriptional and posttranscriptional mechanisms.The tumor suppressor gene, WT1, was identified by positional cloning at chromosome llpl3 on the basis of predisposition to Wilms tumor of the kidney (1, 2). Mutation of WT1 has been associated with abnormalities of the genito-urinary tract, in both humans (reviewed in refs. 3 and 4) and rodents (5, 6), establishing a clear developmental role for the Kruppel-type zinc finger proteins it encodes. Alternative splicing of WTJ results in the production of four variant WT1 proteins that differ by the presence or absence of 17 amino acids, encoded by exon 5, and 3 amino acids (lysine, threonine, and serine; KTS), encoded at the 3' terminus of exon 9 (7). All of the WT1 proteins contain four zinc fingers, which mediate binding to specific DNA sequences, and zinc fingers 2, 3, and 4 are highly homologous with the three zinc fingers of the early growth response factor EGR1 (1, 2, 8, 9). The KTS insertion occurs in the conserved linker region between zinc fingers 3 and 4, such that WT1 variants lacking these three amino acids (WT1-KTS) resemble EGR1 more closely than those in which they are present (WT1 +KTS). Consistent with this is the observation that WT1-KTS binds DNA sequences that resemble the EGR1 consensus-binding site (5'-GCGGGGGCG-3'), whereas WT1+KTS binds more disparate sequences (8-13). In transient transfection assays WT1 can regulate the expression of several growth-related genes containing these motifs (e.g., refs. 14-20), and usually acts as a repressor of these genes. WT1 has thus been described as a transcription factor.We were prompted to examine the possibility of a posttranscriptional regulatory role for WT1 by a number of observations. For maximum effect on at least some of its target genes, WT1-binding sites must be present both upstream and downstream of transcript initiation' sites (14,17,18,21,22). Functional WT1-binding sites are present within 5' untranslated leader sequences of s...